Open Access

Effect of vitamin D supplementation on polycystic ovary syndrome: A meta‑analysis

  • Authors:
    • Chen‑Yun Miao
    • Xiao‑Jie Fang
    • Yun Chen
    • Qin Zhang
  • View Affiliations

  • Published online on: February 11, 2020     https://doi.org/10.3892/etm.2020.8525
  • Pages: 2641-2649
  • Copyright: © Miao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present meta‑analysis was to evaluate the effect of vitamin D supplementation on patients with polycystic ovary syndrome (PCOS). A literature search was performed to identify all of the relevant studies comparing the effect of vitamin D supplementation with placebo in PCOS patients, in the PubMed, Embase and Web of Science databases. All statistical analyses were performed on case‑control studies using Review Manager 5.3 software, provided by the Cochrane Collaboration. A total of 11 studies involving 483 participants were included in the current meta‑analysis. Vitamin D supplementation appeared to lead to an improvement in the levels of total testosterone [weighted mean differences (WMD) = ‑0.10, 95% CI (‑0.18, ‑0.02)], homeostasis model assessment of insulin resistance [WMD = ‑0.44, 95% CI (‑0.86, ‑0.03)], homeostasis model assessment of β‑cell function [WMD = ‑16.65, 95% CI (‑19.49, ‑13.80)], total cholesterol [WMD = ‑11.90, 95% CI (‑15.67, ‑8.13)] and low‑density lipoprotein‑cholesterol [WMD = ‑4.54; 95% CI (‑7.29, ‑1.80)]. The results failed to show a positive effect of vitamin D supplementation on the body mass index, dehydroepiandrosterone sulfate, triglyceride levels or high‑density lipoprotein‑cholesterol. In conclusion, the data from the available randomized controlled trials (RCTs) suggested vitamin D supplementation reduced insulin resistance and hyperandrogenism, as well improving the lipid metabolism of patients with PCOS to an extent. Further high‑quality RCTs from a variety of regions in the world are required to determine the effectiveness of vitamin D supplementation in PCOS patients, and to determine a suitable dose and unit of vitamin D.

Introduction

Polycystic ovary syndrome (PCOS) is a common female endocrine disorder, affecting 6-12% of women of reproductive age globally (1). It is characterized by symptoms such as menstrual irregularity, anovulatory infertility, hyperandrogenism and obesity, as well as metabolic dysfunctions including insulin resistance, type 2 diabetes and dyslipidemia (2). These symptoms can have a serious impact on the quality of life and health of patients. However, due to the complexity of this disease, the pathogenesis remains unclear, and an optimal treatment has not been determined (3). There is a growing need to develop innovative interventions to treat this disease.

Recently, a series of studies have demonstrated that vitamin D deficiency (VDD) is common in patients with PCOS and that VDD may be associated with metabolic and endocrine disorders in PCOS (4-7). Compared with the general population, the prevalence of VDD is relatively higher in PCOS patients (6). Vitamin D is a steroid hormone that is involved in the balance of calcium phosphate and bone mineralization (8). Vitamin D receptors are expressed at 2,776 genomic positions and modulate the expression of 229 genes in more than 30 different tissues, including the pancreas, liver, immune cells, brain and ovaries (9). As a result, vitamin D supplementation for PCOS therapy has attracted attention.

Although a growing number of intervention studies have assessed the relationship between vitamin D supplementation and PCOS, there is a lack of convincing evidence demonstrating the effect of vitamin D supplementation on PCOS. Therefore, the objective of this meta-analysis was to quantitatively summarize the available evidence to assess the effects of vitamin D supplementation on metabolic and hormonal functions in patients with PCOS.

Materials and methods

Data sources and search strategy

In the present study, a systematic search was performed, searching for studies between January 1965 and July 2019 in PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), Embase (https://www.elsevier.com/solutions/embase-biomedical-research), Web of Science (http://webofscience.com) and Ovid Medline (http://ovidsp.ovid.com/). The search was initially conducted using Medical Subject Headings and the following free key words: Polycystic ovary syndrome, polycystic ovary disease, PCOS, calcitriol and vitamin D. Randomized controlled trials (RCTs) investigating the effects of vitamin D supplementation for patients with PCOS were included in the current meta-analysis. A full manual search of the bibliographies of selected studies was performed to identify additional studies.

Inclusion and exclusion criteria

Studies were included if they met the following criteria: A randomized, controlled clinical trial comparing the effects of vitamin D supplementation with placebo; studies that enrolled women with a strict diagnosis of PCOS based on diagnostic criteria produced by the Rotterdam European Society of Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM); the main outcomes included body mass index (BMI), total testosterone, dehydroepiandrosterone sulfate (DHEAs), homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-B), triglycerides, total cholesterol, low density lipoprotein-cholesterol (LDL-C) or low density lipoprotein-cholesterol (HDL-C). For each trial, the most recent data was used in the present analysis.

The exclusion criteria were as follows: Studies reporting other diseases, such as diabetes, Cushing's syndrome, hyperthyroidism or other hormone-related disorders; studies reporting other treatments, such as calcium or metformin; and studies not published in English.

Data extraction

Data extraction and quality assessment were performed by two authors independently. The following information was extracted and entered into a database: The first author's name, year of publication, country, study design, date of accrual, diagnostic criteria for PCOS, the basic characteristics of participants (principal baseline characteristics such as number and age), the control interventions and the main outcomes which included BMI, total testosterone, DHEAs, HOMA-IR, HOMA-B, triglycerides, total cholesterol, LDL-C and HDL-C.

Study quality

The quality of each study was independently assessed by two authors according to the following criteria: Studies designed with case characteristics matched to controls; the studies followed strict inclusion and exclusion criteria for patients; and the methodological quality of the included studies described by Jadad RCT guidelines (a randomized method, concealment allocation, a blinding method and a follow-up) and the Cochrane risk bias assessment tool (10).

Statistical analysis

Continuous data are presented as the mean and SD for all included studies. Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated. In order to measure the heterogeneity among all included studies, Cochran's Q-tests (χ2 test) were used. A Cochran Q-test with P>0.10 and the I2 statistic <50% indicated statistical homogeneity. If the results of the Cochran Q-test favored homogeneity among the studies, the fixed-effect model was used to calculate the total effect size. The random-effects model of meta-analysis was used when unexplained statistical heterogeneity was present. P≤0.05 and a 95% CI not containing 0 (WMD) were considered to be statistically significant. Funnel plots were used to assess publication bias. The current meta-analysis was performed using Review Manager 5.3 software (https://community.cochrane.org/help/tools-and-software/revman-5/revman-5-download/installation) provided by the Cochrane Collaboration.

Results

Study selection

A total of 2,123 relevant studies were obtained in the preliminary examination. After reading the titles and abstracts, 132 related studies were selected. After obtaining the full texts and reviewing them one by one, 121 studies were further excluded. Among them, 76 studies did not conform to the inclusion criteria, 30 studies did not have complete data and 15 studies were of low quality. A total of 11 studies were eventually included. The literature screening process is shown in Fig. 1.

Characteristics of included studies

A total of 11 studies involving 483 participants were included in the meta-analysis. Table I lists the basic characteristics of all included studies. The diagnosis of PCOS in all 11 studies was based on the guidelines of the ESHRE and ASRM. A total of seven studies were conducted in Iran, two were in the United States, one was in India and one was in the UK. A total of 11 studies compared post-intervention differences in metabolic and endocrine parameters between vitamin D supplements and placebo groups.

Table I

Major characteristics measured in the current study.

Table I

Major characteristics measured in the current study.

Authors, yearRCTDate of accrualRegionNo. of patientsAgeSymptomsTreatmentCourseOutcome(Refs.)
Jafari-Sfidvajani et al, 2018YMarch 2016- February 2017Iran3028.43±6.27PCOS, overweight, VDDWeight-loss intervention + 50,000 IU/week oral vitamin D312 weeksBMI, total testosterone, DHEAS(25)
    3027.83±5.71 Weight lossintervention + placebo   
Seyyed Abootorabi et al, 2018Y/Iran1926.21±4.62PCOS, VDD50,000 IU of oral vitamin D38 weeksHOMA-IR, HOMA-B, QUICKI, FPG(26)
    1722.76±4.40 Placebo   
Maktabi et al, 2017YApril 2016 -June 2016Iran3522.0±1.6Phenotype B of PCOS, VDD50,000 IU vitamin D every 2 weeks12 weeksFPG, HOMA-IR, HOMA-B, QUICKI, total testosterone,(27)
    3523.1±3.3 Placebo DHEAS, triglycerides, total cholesterol, LDL-C, HDL-C 
Ardabili et al, 2012YMarch 2010-June 2010Iran2426.8±4.7PCOS, VDD50,000 IU of vitamin D3 every 20 days8 weeksBMI, HOMA, HOMA-IR, QUICKI, FPG(28)
    2627.0±3.7 Placebo   
Raja-Khan et al, 2014YJuly 2009-November 2010USA1128.2±5.2PCOSVitamin D3 12,000 IU daily12 weeksBMI, QUICKI, HOMA-IR, FPG, LDL-C, HDL-C, triglyc(29)
    1128.7±5.6 Placebo erides, total cholesterol, total testosterone 
Garg et al, 2015Y/India1522.0±4.61PCOSMetformin (1,500 mg/day) + vitamin D 4,000 IU/day (monthly dose of 120,000 IU)24 weeksBMI, HOMA-IR, FPG, DHEAs, triglycerides, total cholesterol, LDL-C, HDL-C, total testosterone(30)
    1722.8±4.56 Metformin (1,500 mg/day) + placebo   
Dastorani et al, 2018YDecember 2017-March 2018Iran2029.9±4.4PCOS50,000 IU vitamin D every other week8 weeksFPG, Insulin, HOMA-IR, QUICKI, Triglycerides, Total(31)
    2030.1±3.4 Placebo cholesterol, LDL-C, HDL-C 
Javed et al, 2019Y/UK1828.6±5.5VDDVitamin D 3200 IU daily12 weekshs-CRP, BMI, HOMA-IR,(13)
    1929.1±7.5PCOSPlacebo weight, lipid profile, glucose levels, insulin levels, FAI, testosterone, TC, LDL-C, HDL-C, TG 
Irani et al, 2015YOctober 2013-January 2015USA3530.5±1.0VDD, PCOS50,000 IU of oral vitamin D3 once weekly 8 weeksHOMA-IR, HOMA-B,, triglycerides total cholesterol,(32)
    1829.6±1.7 Placebo once weekly HDL-C, LDL-C, DHEAS, total testosterone 
Foroozanfard et al, 2015YJune-August 2014Iran26/VDD, PCOS50,000 IU vitamin D weekly and calcium placebo daily Calcium placebo daily plus vitamin D placebo weekly8 weeksHOMA-B(33)
Bonakdaran et al, 2012Y/Iran1524.7±3.3PCOSCalcitriol 0.5 µg/day12 weeksTotal testosterone, DHEAS,(34)
    1625.2±7.9 Placebo HOMA-IR 

[i] Y, yes; BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; FPG, fasting plasma glucose; HDL-C, high density lipoprotein-cholesterol ; HOMA, homeostasis model assessment; HOMA-B, homeostasis model assessment of β-cell function; HOMA-IR, homeostasis model assessment of insulin resistance ; IU, international units; LDL-C, low density lipoprotein-cholesterol ; QUICKI, quantitative insulin sensitivity check index; PCOS, polycystic ovary syndrome; RCT, randomized controlled trial; VDD, vitamin D deficiency.

Assessment of bias risk

The quality assessment of eligible studies was accomplished using the Jadad and Cochrane standards. The results are shown in Table II, and Figs. 2 and 3.

Table II

Quality assessment of the included studies using the Jadad Scale.

Table II

Quality assessment of the included studies using the Jadad Scale.

Authors, yearRandomized methodConcealment allocationBlinding methodFollow-upTotal score(Refs.)
Jafari-Sfidvajani et al, 201821216(25)
Seyyed Abootorabi et al, 201811013(26)
Maktabi et al, 201722206(27)
Foroozanfard et al, 201522217(33)
Irani et al, 201511114(32)
Garg et al, 201522116(30)
Raja-Khan et al, 201422217(29)
Ardabili et al, 201222116(28)
Bonakdaran et al, 201211013(34)
Javed et al, 201921205(13)
Dastorani et al, 201821216(31)
Meta-analysis
Effect of vitamin D supplementation on the BMIs of patients with PCOS

A total of five studies were included with the main outcome indicator being the BMI. Heterogeneity tests showed no heterogeneity in each study (χ2=1.00; P=0.91; I2=0%). The results of the meta-analysis using the fixed effect model showed that the BMI of the vitamin D group was not significantly different from that of the placebo group [WMD = 0.00, 95% CI (-0.20, 0.20), P=1.00; Fig. 4].

Effects of vitamin D supplementation on androgen level in patients with PCOS

The main outcome indicators in the present study were total testosterone and DHEA levels. Heterogeneity tests were carried out according to the varying outcome indicators, and the results showed that there was no heterogeneity in either study (χ2=0.79, P=0.94, I2=0%; Fig. 5; χ2=1.42, P=0.84, I2=0%; Fig. 6). The meta-analysis was conducted using the fixed effect model. The results showed that the total testosterone in the vitamin D group was lower than that in the placebo group, and the difference was statistically significant [WMD = -0.10, 95% CI (-0.18, -0.02), P=0.02; Fig. 5]. However, the difference in DHEA levels between the vitamin D group and the placebo group was not statistically significant [WMD = 0.01, 95% CI (-0.04, 0.06), P=0.80; Fig. 6].

Effects of vitamin D supplementation on blood glucose metabolism in patients with PCOS

The outcome indicators that were used to evaluate the effect of vitamin D treatment on the blood glucose metabolism of patients were HOMA-IR and HOMA-B. The heterogeneity test was carried out according to the different outcome indicators, and the results showed that there was moderate heterogeneity among the studies (HOMA-IR, χ2=8.38, P=0.21, I2=28%; HOMA-B, χ2=7.69, P=0.10, I2=48%). The indicators were analyzed using the fixed effect model. Meta-analysis results showed that the HOMA-IR and HOMA-B levels in the vitamin D group were significantly lower than those of the placebo group, and the difference was statistically significant [WMD = -0.44, 95% CI (-0.86, -0.03), P=0.04; Fig. 7; WMD = -16.65, 95% CI (-19.49, -13.80), P<0.01; Fig. 8].

Effects of vitamin D supplementation on lipid metabolism in patients with PCOS

The outcome indicators that were used to evaluate the effect of vitamin D on the lipid metabolism of patients were triglycerides, total cholesterol, LDL-C and HDL-C. The heterogeneity test was carried out according to different outcome indicators, and the results showed that there was no heterogeneity in each study (triglycerides, χ2=0.81, P=0.94, I2=0%; total cholesterol, χ2=5.11, P=0.28, I2=22%; LDL-C, χ2=2.68, P=0.61, I2=0%; HDL-C, χ2=1.83, P=0.77, I2=0%). The meta-analysis was conducted using the fixed effect model. The results showed that the total cholesterol and LDL-C levels of the vitamin D group were significantly lower than those of the placebo group, and that the difference was statistically significant [WMD =- 11.90, 95% CI (-15.67, -8.13), P<0.01; Fig. 9]; WMD = -4.54, 95% CI (-7.29, -1.80), P=0.001; Fig. 10]. However, the difference in the triglyceride and HDL-C levels between the vitamin D group and the placebo group was not statistically significant [WMD = -5.59, 95% CI (-12.11, 0.93), P=0.09; Fig. 11; WMD = -0.43, 95% CI (-1.56, 0.69), P=0.45; Fig. 12].

Sensitivity analyses and publication bias

Sensitivity analyses were performed to evaluate the stability of the results using the random-effect method. The results showed that there was no significant change when any one of the studies was excluded from the total analyses. Funnel plots were used to evaluate the significance of publication bias. The results of the funnel plots showed that there was no significant publication bias for HDL-C (Fig. S1), HOMA-IR (Fig. S3), LDL-C (Fig. S4), total testosterone (Fig. S6), BMI (Fig. S8) and DHEAs (Fig. S9). However, publication biases were found in HOMA-B (Fig. S2), total cholesterol (Fig. S5) and triglycerides (Fig. S7).

Discussion

The current meta-analysis of RCTs was designed to determine the efficacy of vitamin D supplementation in PCOS. HOMA-IR, HOMA-B are both important factors in the development of diabetes, and are also used as one of the main methods to measure insulin sensitivity (11,12). In regards to lipid metabolism, LDL-C, HDL-C, triglycerides and total cholesterol are common indicators of the lipid profile of a patient, and LDL-C is an independent risk factor for cardiovascular disease (13). Evidence from the current results suggested that the use of vitamin D, as a treatment for patients with PCOS, could improve insulin resistance, hyperandrogenism and a number of the lipid metabolic parameters in PCOS patients in the short-term follow-up intervention.

These outcomes are consistent with several previous reports. Several similar studies (14-16) have demonstrated that vitamin D supplementation therapy has a beneficial effect on insulin resistance in women with PCOS. Wehr et al (17) found that after 12 weeks of vitamin D treatment, total cholesterol and LDL-C levels significantly increased, while there was no obvious change in HDL-C and triglycerides levels. Following 24 weeks of intervention, significant changes were observed in the levels of total cholesterol, LDL-C and triglycerides. According to this study, some of the non-significant results may be attributed to the short duration of the intervention. A previous meta-analysis by Azadi-Yazdi et al (18) suggested that vitamin D supplementation may significantly affect the serum total testosterone, whilst not being effective in improving other markers of the androgenic profile. These results are consistent with the results of the present study.

Insulin resistance is defined decreased sensitivity of tissues to insulin, thereby resulting in reduced glucose utilization. As glucose does not enter the target cells, serum glucose concentrations increase, which stimulates pancreatic β-cells to secrete more insulin into the blood. It is generally considered that insulin resistance plays an pivotal role in the pathogenesis of PCOS (19). Insulin resistance is associated with the development of impaired glucose tolerance and type 2 diabetes, as well as affecting lipid metabolism (20). However, insulin resistance also increases hyperandrogenism by affecting the production of hepatic sex hormone-binding globulin (21). Vitamin D may contribute to the development of insulin resistance by enhancing PPARγ expression, which enhances insulin synthesis and release, and vitamin D may promote insulin receptor expression or suppression of proinflammatory cytokines (9,22,23).

However, a 2016 meta-analysis (24) reported that vitamin D supplementation did not influence the glucose and lipid metabolic parameters in PCOS patients. Due to the different interventions of the included studies, the result of the present meta-analysis is different from that of the 2016 meta-analysis, in which the intervention method was vitamin D supplementation or metformin.

The current meta-analysis had a number of strengths, including a comprehensive literature search, specified inclusion and exclusion criteria, explicit methods for data extraction and the inclusion of measures taken to properly reduce the influence of bias and to assess heterogeneity. However, despite these strengths, the current meta-analysis also had a number of limitations. Firstly, the number of studies available for each meta-analysis was less than seven, which may be too small for the assessment of publication bias through funnel plots. Most studies examined had a small sample size and short term follow-ups. There were also many variations among studies such as doses and units of vitamin D that were used, as well as the duration of interventions. The present study was unable to investigate the curative effects of different doses and treatment durations. Furthermore, varying levels of exposure to sunlight may have had an impact on the analysis, which may have affected the quality of the results. A number of the studies also did not apply appropriate randomization and allocation concealment, thus there is a risk of selection bias.

In conclusion, despite several limitations, the present study found that vitamin D supplementation could affect insulin resistance, lipid metabolism and, to an extent, hyperandrogenism in patients with PCOS. Therefore, vitamin D should be considered as a treatment for PCOS. There is a strong need for further research to directly validate the results of the present study. Further studies should include large sample sizes and long-term interventions, with double-blind placebo controls. It would also be of benefit to perform these studies worldwide, especially in areas where women are exposed to abundant sunlight. Additionally, it would be of interest to the effects of vitamin D on the induction of ovulation or menstrual cycle regulation in patients with PCOS. Further experiments should also be designed to explore the pathogenesis between vitamin D and PCOS. Finally, an optimal dose of vitamin D should be determined to allow for an effective therapy to be developed.

Supplementary Material

Figure S1. Funnel plot for HDL-C. The funnel plot shows the publication bias of HDL-C. The majority of the studies were concentrated at the top of the funnel plot, and each study was symmetrically distributed. There was no obvious publication bias. HDL-C, high density lipoprotein-cholesterol; MD, mean difference; SE, standard error.
Figure S2. Funnel plot for HOMA-B. The funnel plot shows the publication bias of HOMA-B. Three of the studies were distributed at the top of the funnel plot. Two of the studies were scattered, showing the existence of publication bias. HOMA-B, homeostasis model assessment of β-cell function; MD, mean difference; SE, standard error.
Figure S3. Funnel plot for HOMA-IR. The funnel plot shows the publication bias of HOMA-IR. Most of the studies were concentrated at the top of the funnel plot, and each study was symmetrically distributed. There was no obvious publication bias. HOMA-IR, homeostasis model assessment of insulin resistance; MD, mean difference; SE, standard error.
Figure S4. Funnel plot for LDL-C. The funnel plot shows the publication bias of LDL-C. Most of the studies were concentrated at the top of the funnel plot, and each study was symmetrically distributed. There was no obvious publication bias. LDL-C, low density lipoprotein-cholesterol; MD, mean difference; SE, standard error.
Figure S5. Funnel plot for total cholesterol. The funnel plot shows the publication bias of total cholesterol. Most of the studies were concentrated on one side, showing the existence of publication bias. MD, mean difference; SE, standard error.
Figure S6. Funnel plot for total testosterone: The funnel plot shows the publication bias of total testosterone. Each study was symmetrically distributed. There was no obvious publication bias. MD, mean difference; SE, standard error.
Figure S7. Funnel plot for triglycerides. The funnel plot shows the publication bias of triglycerides. Three of the studies were distributed at the top of the funnel plot. Two of the studies were concentrated on one side, showing the existence of publication bias. MD, mean difference; SE, standard error.
Figure S8. Funnel plot for BMI. The funnel plot shows the publication bias of BMI. Each study was symmetrically distributed. There was no obvious publication bias. BMI, body mass index; MD, mean difference; SE, standard error.
Figure S9. Funnel plot for DHEAs. The funnel plot shows the publication bias of DHEAs. Each study was symmetrically distributed. There was no obvious publication bias. DHEA, dehydroepiandrosterone sulfate; MD, mean difference; SE, standard error.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

CYM and XJF were involved in data management and statistics, and drafted the manuscript. QZ and YC verifed the extracted data following the literature search, monitored the study and drafted the manuscript. QZ deisgned the current study. XJF and YC conducted the searches and performed statistical anlaysis. QZ and CYM performed extracted the data and contributed to quality assessment. All authors contributed to drafting and revising the manuscript and all authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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April-2020
Volume 19 Issue 4

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Spandidos Publications style
Miao CY, Fang XJ, Chen Y and Zhang Q: Effect of vitamin D supplementation on polycystic ovary syndrome: A meta‑analysis. Exp Ther Med 19: 2641-2649, 2020
APA
Miao, C., Fang, X., Chen, Y., & Zhang, Q. (2020). Effect of vitamin D supplementation on polycystic ovary syndrome: A meta‑analysis. Experimental and Therapeutic Medicine, 19, 2641-2649. https://doi.org/10.3892/etm.2020.8525
MLA
Miao, C., Fang, X., Chen, Y., Zhang, Q."Effect of vitamin D supplementation on polycystic ovary syndrome: A meta‑analysis". Experimental and Therapeutic Medicine 19.4 (2020): 2641-2649.
Chicago
Miao, C., Fang, X., Chen, Y., Zhang, Q."Effect of vitamin D supplementation on polycystic ovary syndrome: A meta‑analysis". Experimental and Therapeutic Medicine 19, no. 4 (2020): 2641-2649. https://doi.org/10.3892/etm.2020.8525