![Forest plot showing the overall effect of zinc supplementation on pain severity using the longest follow-up data [12,13,23,24,25,26].](https://www.researchgate.net/publication/386229266/figure/fig3/AS:11431281297558507@1734141622424/Forest-plot-showing-the-overall-effect-of-zinc-supplementation-on-pain-severity-using-the_Q320.jpg)
![Forest plot for the subgroup analysis using the follow-up duration as the moderator, including one, two, and three months. The directions of association between zinc supplementation and pain scale assessment were consistent across all follow-up durations, with overlapping 95% confidence intervals (CIs), indicating similar trends in pain reduction over time despite varying levels of statistical significance and heterogeneity [12,13,23,24,25,26].](https://www.researchgate.net/publication/386229266/figure/fig4/AS:11431281297599325@1734141622697/Forest-plot-for-the-subgroup-analysis-using-the-follow-up-duration-as-the-moderator_Q320.jpg)
Access to this full-text is provided by MDPI.
Content available from Nutrients
This content is subject to copyright.
Citation: Hsu, T.-J.; Hsieh, R.-H.;
Huang, C.-H.; Chen, C.-S.; Lin, W.-Y.;
Huang, Y.-C.; Lin, J.-H.; Huang, K.-T.;
Liu, Y.-L.; Tsai, H.-M.; et al. Efficacy of
Zinc Supplementation in the
Management of Primary Dysmenorrhea:
A Systematic Review and Meta-
Analysis. Nutrients 2024,16, 4116.
https://doi.org/10.3390/nu16234116
Academic Editors: Maria Luz
Fernandez and Alan Stewart
Received: 19 October 2024
Revised: 14 November 2024
Accepted: 27 November 2024
Published: 28 November 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Systematic Review
Efficacy of Zinc Supplementation in the Management of Primary
Dysmenorrhea: A Systematic Review and Meta-Analysis
Ting-Jui Hsu 1, Rong-Hong Hsieh 2,3,4, Chin-Huan Huang 5, Chih-Shou Chen 1, Wei-Yu Lin 1,6,
Yun-Ching Huang 1,7, Jian-Hui Lin 1,7,8, Kuo-Tsai Huang 1, Yu-Liang Liu 1, Hui-Ming Tsai 2 ,5 ,*
and Dong-Ru Ho 1,7,9,*
1Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
tony110681@cgmh.org.tw (T.-J.H.); cgmh5093@gmail.com (C.-S.C.); checotrade@gmail.com (W.-Y.L.);
dr5326@cgmh.org.tw (Y.-C.H.); b9005026@gmail.com (J.-H.L.); ronsolglobalinc@gmail.com (K.-T.H.);
armsliu@cgmh.org.tw (Y.-L.L.)
2School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University,
Taipei 11031, Taiwan; hsiehrh@tmu.edu.tw
3Research Center of Nutritional Medicine, College of Nutrition, Taipei Medical University,
Taipei 11031, Taiwan
4Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University,
Taipei 11031, Taiwan
5Department of Nutrition Therapy, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation,
Chiayi 622401, Taiwan; dalinrd@tzuchi.com.tw
6School of Medicine, National Cheng Kung University, Tainan City 701401, Taiwan
7Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University,
Taoyuan 33302, Taiwan
8
Department of Early Childhood Care and Education, Shu-Zen Junior College of Medicine and Management,
Kaohsiung City 82144, Taiwan
9School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan
*Correspondence: ga56112003@tmu.edu.tw (H.-M.T.); redoxdrh@gmail.com (D.-R.H.)
Abstract: Background/Objectives: Primary dysmenorrhea (PD) is a common condition affecting
up to 90% of menstruating women, which often results in significant pain without an underlying
pathology. Zinc, recognized for its anti-inflammatory and antioxidant effects through inhibiting
prostaglandin production and superoxide dismutase 1 (SOD1) upregulation, alleviates menstrual
pain by preventing uterine spasms and enhancing microcirculation in the endometrium, suggesting
its potential as an alternative treatment for primary dysmenorrhea. The goal of this systematic review
and meta-analysis was to assess the efficacy and safety of zinc supplementation in reducing pain
severity among women with PD and to explore the influence of dosage and treatment duration.
Methods: Following the PRISMA 2020 guidelines, we conducted an extensive search across databases
such as PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar, up to May 2024.
Randomized controlled trials assessing the effects of zinc supplementation on pain severity in
women with PD were included. Pain severity was evaluated with established tools, such as the
Visual Analog Scale (VAS). Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB2)
tool. Two reviewers independently performed the data extraction, and a random-effects model was
used for meta-analysis. Meta-regressions were conducted to examine the influence of zinc dosage
and treatment duration on pain reduction. Adverse events were also analyzed. Results: Six RCTs
involving
739 participants
met the inclusion criteria. Zinc supplementation significantly reduced pain
severity compared to placebo (Hedges’s g =
−
1.541; 95% CI:
−
2.268 to
−
0.814;
p< 0.001
), representing
a clinically meaningful reduction in pain. Meta-regression indicated that longer treatment durations
(
≥
8 weeks) were associated with greater pain reduction (p= 0.003). While higher zinc doses provided
additional pain relief, the incremental benefit per additional milligram was modest (regression
coefficient = −0.02 per mg;
p= 0.005). Adverse event rates did not differ significantly between
the zinc and placebo groups (odds ratio = 2.54; 95% CI: 0.78 to 8.26; p= 0.122), suggesting good
tolerability. Conclusions: Zinc supplementation is an effective and well-tolerated option for reducing
pain severity in women with primary dysmenorrhea. Doses as low as 7 mg/day of elemental zinc
Nutrients 2024,16, 4116. https://doi.org/10.3390/nu16234116 https://www.mdpi.com/journal/nutrients
Nutrients 2024,16, 4116 2 of 17
are sufficient to achieve significant pain relief, with longer durations (≥8 weeks) enhancing efficacy.
The favorable safety profile and ease of use support the consideration of zinc supplementation as a
practical approach to managing primary dysmenorrhea.
Keywords: zinc supplementation; primary dysmenorrhea; menstrual pain; pain relief; anti-inflammatory;
women’s health; randomized controlled trials; meta-analysis; nutritional supplements
1. Introduction
Primary dysmenorrhea (PD) is characterized by cramp-like pain in the lower abdomen
that occurs just before or at the onset of menstruation, without any identifiable pelvic
pathology. PD affects 45% to 95% of reproductive-aged women worldwide, with 2% to 29%
reporting severe pain that can significantly impair daily activities [
1
]. Besides lower abdom-
inal pain, PD is often associated with symptoms, including headache, back and thigh pain,
fatigue, nausea, vomiting, and diarrhea [
2
,
3
]. The exact etiology of PD remains not entirely
understood, but it is generally attributed to the excessive production of prostaglandin F2
α
(PGF2
α
) and leukotrienes in the endometrium during menstruation, which lead to intense
or irregular uterine muscle contractions and vasoconstriction, resulting in uterine ischemia
and pain [4–6].
Current management strategies for PD primarily involve the administration of non-
steroidal anti-inflammatory drugs (NSAIDs) [
7
,
8
]. However, long-term use can lead to side
effects, such as gastrointestinal disturbances, nausea, vomiting, and dizziness [3].
Given the substantial medical, social, and economic burden of PD, there is a pressing
need to identify effective treatments with fewer side effects and better tolerability than
current options.
Zinc, an essential trace element involved in numerous enzymatic reactions, has at-
tracted attention for its potential role in reproductive health [
9
,
10
]. Zinc has been shown to
modulate cyclooxygenase activity and inhibit prostaglandin synthesis, to enhance microcir-
culation and prevent ischemia in uterine tissues, and to exhibit antioxidant properties by in-
creasing superoxide dismutase levels and downregulating inflammatory cytokines [
10
,
11
].
Recent studies have suggested that zinc supplementation can significantly reduce the
severity and duration of dysmenorrhea symptoms compared to placebo [
12
,
13
]. Addition-
ally, Nasiadek et al. (2020) [
9
] emphasized the importance of zinc in disorders of the female
reproductive system, highlighting its importance in modulating inflammatory responses
and hormonal regulation, which are critical factors in the pathogenesis of PD.
Considering the increasing evidence supporting the beneficial effects of zinc on PD,
a systematic review and meta-analysis are warranted to evaluate the efficacy and safety
of zinc supplementation for managing primary dysmenorrhea. This study aims to assess
the impact of zinc supplementation on pain severity and associated symptoms, analyze
the influence of dosage and treatment duration, and provide reliable evidence to inform
clinical practice.
2. Materials and Methods
2.1. General Guidelines
This systematic review and meta-analysis adhered to the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines
Supplementary Table S1 [14].
The study protocol was registered in PROSPERO with the registration number
CRD42024579213 [
15
]. No ethical approval or informed consent was required since the
study utilized previously published data.
2.2. Search Strategy and Selection of Eligible Studies
Two independent authors (T.-J.H. and H.-M.T.) performed extensive database searches
in the PubMed, Cochrane Library, Embase, Web of Science, and Google Scholar databases
Nutrients 2024,16, 4116 3 of 17
using the following keywords: (“Zinc Supplementation” OR “Zinc therapy” OR “Zinc sul-
fate” OR “Oral zinc”) AND (“Primary Dysmenorrhea” OR “Menstrual pain” OR “Menstrual
cramps” OR “Period pain” OR “Dysmenorrhoea”) AND (“Randomized Controlled Trial”
OR “Clinical trial” OR “RCT” OR “Randomised trial”). The search covered all publications
up to 24 August 2024. Additionally, we performed a hand search of the reference lists of rel-
evant articles to find any other eligible studies. Studies published in English were included.
The detailed search strategy is provided in the Supplementary Materials Table S2.
2.3. Inclusion and Exclusion Criteria
The meta-analysis was structured using the PICO (Population, Intervention, Compari-
son, Outcome) framework: Population (P): women diagnosed with primary dysmenorrhea;
Intervention (I): zinc supplementation alone or combined with other treatments (e.g.,
NSAIDs), in any form and dosage; Comparison (C): placebo, or other treatments (e.g.,
NSAIDs) plus placebo; and Outcome (O): outcomes related to pain severity.
The criteria for inclusion were as follows: (1) randomized controlled trials (RCTs),
(2) studies
evaluating the efficacy of zinc supplementation in primary dysmenorrhea, and
(3) studies reporting outcomes related to pain severity.
The criteria for exclusion included the following: (1) studies involving secondary
dysmenorrhea; (2) observational studies, reviews, and case reports; and (3) studies with
incomplete data or non-comparable outcomes.
The detailed inclusion and exclusion criteria, along with their explanations, are pro-
vided in the Supplementary Materials Table S3.
2.4. Methodological Quality Appraisal
We evaluated the quality of the methodologies in the selected studies using the
Cochrane Risk of Bias tool for randomized trials (version 2, RoB 2) [
16
]. This tool evaluates
six domains: the randomization process, deviations from intended interventions, missing
outcome data, measurement of the outcome, selection of the reported result, and overall
risk of bias. Two reviewers (T.-J.H. and H.-M.T.) independently assessed each study, and
any disagreements were addressed through discussion or by consulting a third reviewer
(R.-H.H).
2.5. Primary Outcome
The primary outcome measured was the change in pain severity associated with
primary dysmenorrhea, assessed using validated pain scales like the Visual Analog Scale
(VAS) [
17
] or the Numeric Rating Scale (NRS) [
18
]. If multiple pain assessments were
reported, the most commonly used scale across studies was selected for analysis.
2.6. Secondary Outcome
The secondary outcome examined in this analysis was the incidence of adverse events
related to the treatment. Odds ratios were used to quantify these outcomes.
2.7. Data Extraction and Management
Two independent reviewers (T.-J.H. and H.-M.T.) gathered data through a standard-
ized form. The extracted details encompassed study characteristics (authors, year of
publication, and country), participant demographics, intervention details (zinc dosage,
form, and duration), comparison interventions, outcome measures, and results. Any incon-
sistencies were settled by reaching an agreement or by involving a third reviewer. When
necessary, we contacted study authors for additional information or clarification.
2.8. Statistical Analyses
The statistical evaluations were conducted using Comprehensive Meta-Analysis soft-
ware (version 3.7; Biostat, Englewood, NJ, USA). For continuous outcomes, we calculated
Hedges’s g with 95% confidence intervals (CIs). Hedges’s g values of 0.2, 0.5, and 0.8
Nutrients 2024,16, 4116 4 of 17
were considered to represent small, moderate, and large effect sizes, respectively [
19
]. For
dichotomous outcomes, odds ratios (ORs) with 95% CIs were determined.
The variability among studies was evaluated using the I
2
statistic and Cochran’s Q
test. I
2
statistics of 25%, 50%, and 75% were interpreted as indicating low, moderate, and
high heterogeneity, respectively [
20
]. Due to the anticipated differences among studies, a
random-effects model was applied [21].
Subgroup analyses were carried out based on treatment duration. Meta-regression
analyses were performed to investigate the association between treatment effects and
factors such as daily zinc dosage and the length of supplementation.
Sensitivity analysis was conducted using the one-study removal method to determine
whether excluding any single trial would result in a statistically significant change in
the overall effect size. Publication bias was assessed through funnel plots and Egger’s
regression test. Egger’s regression test was applicable when the meta-analysis included ten
or more studies [22].
3. Results
3.1. Study Identification and Selection
The PRISMA diagram detailing the procedures for literature searching and study
selection is displayed in Figure 1. After eliminating duplicate entries and reviewing titles
and abstracts, we identified six randomized controlled trials (RCTs) that fulfilled the
inclusion criteria for this meta-analysis [
12
,
13
,
23
–
26
]. The articles that were excluded in
the final stage, along with the reasons for their exclusion, are listed in the Supplementary
Materials Table S4. The detailed data extracted from the included trials are summarized in
the Supplementary Materials Table S5. The features of the studies included in this analysis
are summarized in Table 1. The intervention details, dosage of zinc supplements, tools for
pain assessment, and study withdrawals are summarized in Table 2.
Nutrients 2024, 16, x FOR PEER REVIEW 4 of 16
2.8. Statistical Analyses
The statistical evaluations were conducted using Comprehensive Meta-Analysis soft-
ware (version 3.7; Biostat, Englewood, NJ, USA). For continuous outcomes, we calculated
Hedges’ g with 95% condence intervals (CIs). Hedges’ g values of 0.2, 0.5, and 0.8 were
considered to represent small, moderate, and large eect sizes, respectively [19]. For di-
chotomous outcomes, odds ratios (ORs) with 95% CIs were determined.
The variability among studies was evaluated using the I2 statistic and Cochran’s Q
test. I2 statistics of 25%, 50%, and 75% were interpreted as indicating low, moderate, and
high heterogeneity, respectively [20]. Due to the anticipated dierences among studies, a
random-eects model was applied [21].
Subgroup analyses were carried out based on treatment duration. Meta-regression
analyses were performed to investigate the association between treatment eects and fac-
tors such as daily zinc dosage and the length of supplementation.
Sensitivity analysis was conducted using the one-study removal method to deter-
mine whether excluding any single trial would result in a statistically signicant change
in the overall eect size. Publication bias was assessed through funnel plots and Egger’s
regression test. Egger’s regression test was applicable when the meta-analysis included
ten or more studies [22].
3. Results
3.1. Study Identication and Selection
The PRISMA diagram detailing the procedures for literature searching and study se-
lection is displayed in Figure 1. After eliminating duplicate entries and reviewing titles
and abstracts, we identied six randomized controlled trials (RCTs) that fullled the in-
clusion criteria for this meta-analysis [12,13,23–26]. The articles that were excluded in the
nal stage, along with the reasons for their exclusion, are listed in the Supplementary Ma-
terials Table S4. The detailed data extracted from the included trials are summarized in
the Supplementary Materials Table S5. The features of the studies included in this analysis
are summarized in Table 1. The intervention details, dosage of zinc supplements, tools for
pain assessment, and study withdrawals are summarized in Table 2.
Figure 1. PRISMA 2020 diagram summarizing the study selection process for this meta-analysis.
Figure 1. PRISMA 2020 diagram summarizing the study selection process for this meta-analysis.
Nutrients 2024,16, 4116 5 of 17
Table 1. Summary of the trials examining the effect of zinc supplementation on managing primary dysmenorrhea among the participants.
First Author
and Year Country Population Participants (Female) Age 1Study Design Allocation
Concealment Randomization
Funding/Grants/Support
Kashefi 2014 [23] Iran Healthy subjects
with PD
Ginger: 48 2
Zinc sulfate: 56
Placebo: 46
17 ±0.43 2RCT, double-blind Not mentioned Random table Bojnurd University of
Medical Science
Sangestani 2015 [24] Iran Healthy subjects
with PD
Zinc sulfate: 34 2,3
Placebo: 32
21.5 ±2.5 2,3
21.7 ±2.2 RCT, double-blind Not mentioned Not mentioned N/A
Zekavat 2015 [25] Iran Healthy subjects
with PD
Zinc sulfate: 60 2,3
Placebo: 60
15.2 ±1.7 2,3
14.8 ±2.1 RCT, double-blind Concealed envelope
Computer-based
random digit
generator
N/A
Teimoori 2016 [26] Iran Healthy subjects
with PD
Zinc sulfate +
mefenamic acid: 100
2,3
Placebo + mefenamic
acid: 100
21.6 ±2.1 2,3
21.3 ±2.0 RCT, double-blind Not mentioned
Computer-based
random digit
generator
N/A
Safdar 2022 [13] Pakistan Healthy subjects
with PD
Zinc gluconate: 50 2,3
Placebo: 50
21.3 ±1.86 2,3
20.78 ±2.01 RCT, single-blind Not mentioned Lottery method N/A
Obiagwu 2023 [12] Nigeria Healthy subjects
with PD
Zinc sulfate: 50 3
Placebo: 50 15.89 ±1.54 3RCT, double-blind
Independent third
party with concealed
envelope
Random number
table N/A
PD, primary dysmenorrhea; RCT, randomized controlled trial. 1Age is provided in the form of mean ±standard deviation. 2Allocated participants. 3Per-protocol participants.
Nutrients 2024,16, 4116 6 of 17
Table 2. Summary of the zinc supplement interventions administered in the treatment arms of the included trials.
First Author
and Year Population Duration Zinc Supple-
ment/Manufacturer
Daily Zinc Dose 1
(Per-Protocol N)
Control
(Per-Protocol N)
Pain Measurement
(Score Range)
AE Associated with
Zinc Supplement
Withdrawal
Kashefi 2014 [23]Healthy high-school
students with PD 1 and 2 months
Zinc sulfate
capsules/Department
of Industrial Pharmacy
in the Faculty of
Pharmacy (Iran)
150 mg/day 2(53) Matching placebo (42)
Pain Visual
Analog Scale
(0–10)
Not mentioned
Sangestani 2015 [24]Healthy university
students with PD 1 month Zinc sulfate/Not
mentioned 30 mg/day 3(34) Matching placebo (32)
Pain Visual
Analog Scale
(0–100)
No
Zekavat 2015 [25]Adolescent females
with PD 1, 2, and 3 months
Zinc sulfate
capsules/Alhavi Drug
Company (Iran)
15 mg/day 4(60) Matching placebo (60)
Pain Visual
Analog Scale
(0–10)
No
Teimoori 2016 [26]Healthy university
students with PD 3 months Zinc sulfate/Not
mentioned
50 mg/day 5+
mefenamic acid
750 mg/day (100)
Matching placebo +
mefenamic acid
750 mg/day (100)
Pain Visual
Analog Scale
(0–10)
No
Safdar 2022 [13]Healthy women
with PD 3 and 6 months Zinc gluconate/Not
mentioned 7 mg/day 6(50) Matching placebo (50)
Pain Visual
Analog Scale
(0–10)
No
Obiagwu 2023 [12]Healthy high-school
students with PD 1, 2, and 3 months
Zinc sulfate/Chi
Pharmaceutical
Company (Nigeria)
9.2 mg/day 7(50) Matching placebo (50)
Pain Visual
Analog Scale
(0–10)
No. All withdrawals
were not associated
with the study
intervention
AE, adverse event; PD, primary dysmenorrhea.
1
Zinc supplement dosages were standardized to elemental zinc, with zinc sulfate containing 23% and zinc gluconate 14.3% elemental
zinc [
27
].
2
Three times a day for four days, starting from the day before menstrual bleeding to the third day of menstrual bleeding.
3
Twice per day for a period of four days before the
onset of menstruation.
4
One capsule per night during the intervention.
5
Zinc sulfate capsules once daily and mefenamic acid capsules (250 mg) three times daily, starting three days
before menstruation and continuing for three days after.
6
Once daily for seven days, starting from five days before the estimated date of menstruation and two days after the onset of
menstruation. 7Once daily for three days, starting on the first day of menstruation and continuing until the third day of menstrual bleeding.
Nutrients 2024,16, 4116 7 of 17
The six included RCTs encompassed a total of 739 participants aged between 13 and
27 years,
all of whom were women diagnosed with primary dysmenorrhea. The studies
were conducted in different countries, including Iran, Nigeria, and Pakistan, and had
treatment durations ranging from one to six months. However, these trials did not report
participants’ dietary zinc intake, zinc status, or overall nutritional status, such as BMI or
biochemical markers. Therefore, we are unable to determine the nutritional status of the
participants or whether they had zinc deficiency.
3.2. Methodological Quality of the Included Studies
The methodological quality of the included studies was assessed using the Cochrane
Risk of Bias tool for randomized trials (RoB 2) [
16
]. The overall risk of bias was mixed:
33% of the studies were rated as having a low risk of bias, and 67% had some concerns
Figure 2. Common issues included insufficient details on randomization and allocation
concealment, as well as insufficient handling of missing outcome data in some studies.
Detailed assessments are provided in Table 3.
Nutrients 2024, 16, 4116 6 of 16
3.2. Methodological Quality of the Included Studies
The methodological quality of the included studies was assessed using the Cochrane
Risk of Bias tool for randomized trials (RoB 2) [16]. The overall risk of bias was mixed:
33% of the studies were rated as having a low risk of bias, and 67% had some concerns
Figure 2. Common issues included insufficient details on randomization and allocation
concealment, as well as insufficient handling of missing outcome data in some studies.
Detailed assessments are provided in Table 3.
Table 3. Detailed quality assessment of included studies using the Cochrane Risk of Bias 2 tool.
First Author Year
Randomization
Process
Intervention
Adherence
Missing
Outcome Data
Outcome
Measurement
Selective
Reporting
Overall
RoB
Kashefi [23]
2004
S
1
L
S
2
L
L
S
Sangestani [24]
2015
S
1
L
L
L
L
S
Zekavat [25]
2015
L
L
L
L
L
L
Teimoori [26]
2016
S
1
L
L
L
L
S
Safdar [13]
2022
S
1
L
L
L
L
S
Obiagwu [12]
2023
L
L
L
L
L
L
1 The studies did not provide allocation concealment details. 2 The study had a moderate proportion
of missing data (7 out of 102 participants), with unclear reasons for dropout and insufficient han-
dling of missing data. H, high risk of bias; S, some risk of bias; L, low risk of bias; RoB, risk of bias.
Figure 2. Quality assessment summary for studies included in the meta-analysis, evaluated using
the Cochrane Risk of Bias 2 tool.
3.3. Primary Outcome: Effects of Zinc Supplementation on Pain Severity
Using the longest follow-up data from each study, we performed a meta-analysis to
evaluate the effectiveness of zinc supplementation in reducing pain severity among
women with primary dysmenorrhea. The pooled analysis of all six studies demonstrated
a statistically significant reduction in pain severity with zinc supplementation compared
to placebo (Hedges’s g = −1.541; 95% CI = −2.268 to −0.814; p < 0.001; I2 = 94.31%; Q = 87.918)
Figure 3. The effect size indicates a large reduction in pain severity associated with zinc
supplementation.
Figure 2. Quality assessment summary for studies included in the meta-analysis, evaluated using the
Cochrane Risk of Bias 2 tool.
Table 3. Detailed quality assessment of included studies using the Cochrane Risk of Bias 2 tool.
First Author Year
Randomization
Process
Intervention
Adherence
Missing
Outcome Data
Outcome
Measurement
Selective
Reporting
Overall
RoB
Kashefi [23] 2004 S1LS2L L S
Sangestani [24] 2015 S1LLLLS
Zekavat [25] 2015 L L L L L L
Teimoori [26] 2016 S1LLLLS
Safdar [13] 2022 S1LLLLS
Obiagwu [12] 2023 L L L L L L
1
The studies did not provide allocation concealment details.
2
The study had a moderate proportion of missing
data (7 out of 102 participants), with unclear reasons for dropout and insufficient handling of missing data. H,
high risk of bias; S, some risk of bias; L, low risk of bias; RoB, risk of bias.
3.3. Primary Outcome: Effects of Zinc Supplementation on Pain Severity
Using the longest follow-up data from each study, we performed a meta-analysis
to evaluate the effectiveness of zinc supplementation in reducing pain severity among
women with primary dysmenorrhea. The pooled analysis of all six studies demonstrated
a statistically significant reduction in pain severity with zinc supplementation compared
to placebo (Hedges’s g =
−
1.541; 95% CI =
−
2.268 to
−
0.814; p< 0.001; I
2
= 94.31%;
Q = 87.918
) Figure 3. The effect size indicates a large reduction in pain severity associated
with zinc supplementation.
Nutrients 2024,16, 4116 8 of 17
Nutrients 2024, 16, 4116 7 of 16
Figure 3. Forest plot showing the overall effect of zinc supplementation on pain severity using the
longest follow-up data [12,13,23–26].
Given the high heterogeneity observed among the studies (I2 = 94.31%), we explored
possible contributors to heterogeneity through subgroup analyses and meta-regressions.
We first performed a subgroup analysis based on follow-up duration Figure 4.
Figure 4. Forest plot for the subgroup analysis using the follow-up duration as the moderator, in-
cluding one, two, and three months. The directions of association between zinc supplementation
and pain scale assessment were consistent across all follow-up durations, with overlapping 95%
confidence intervals (CIs), indicating similar trends in pain reduction over time despite varying lev-
els of statistical significance and heterogeneity [12,13,23–26].
At the 1-month follow-up, four studies [12,23–25] reported outcomes. The pooled ef-
fect size was Hedges’s g = −0.529 (95% CI = −1.163 to 0.105; p = 0.102; I2 = 77.6%). This
indicates a moderate reduction in pain severity at 1 month with zinc supplementation;
however, the result did not reach statistical significance at the 0.05 level.
At the 2-month follow-up, three studies [12,23,25] provided data. The pooled effect
size was Hedges’s g = −1.409 (95% CI = −2.146 to −0.672; p < 0.001; I2 = 95.7%), suggesting a
large reduction in pain severity at 2 months.
At the 3-month follow-up, four studies [12,13,25,26] reported outcomes. The pooled
effect size was Hedges’s g = −1.068 (95% CI = −1.697 to −0.439; p = 0.001; I2 = 85.2%), demon-
strating a sustained large reduction in pain severity at 3 months.
To investigate the relationship between treatment duration and effect size, a meta-
regression was performed using follow-up time (in months) as a continuous moderator.
The analysis revealed a significant association between longer treatment duration and
greater reductions in pain severity (regression coefficient = −0.452 per month; p < 0.001)
Figure 5. This suggests that the efficacy of zinc supplementation increases with longer
treatment periods.
Figure 3. Forest plot showing the overall effect of zinc supplementation on pain severity using the
longest follow-up data [12,13,23–26].
Given the high heterogeneity observed among the studies (I
2
= 94.31%), we explored
possible contributors to heterogeneity through subgroup analyses and meta-regressions.
We first performed a subgroup analysis based on follow-up duration Figure 4.
Nutrients 2024, 16, 4116 7 of 16
Figure 3. Forest plot showing the overall effect of zinc supplementation on pain severity using the
longest follow-up data [12,13,23–26].
Given the high heterogeneity observed among the studies (I2 = 94.31%), we explored
possible contributors to heterogeneity through subgroup analyses and meta-regressions.
We first performed a subgroup analysis based on follow-up duration Figure 4.
Figure 4. Forest plot for the subgroup analysis using the follow-up duration as the moderator, in-
cluding one, two, and three months. The directions of association between zinc supplementation
and pain scale assessment were consistent across all follow-up durations, with overlapping 95%
confidence intervals (CIs), indicating similar trends in pain reduction over time despite varying lev-
els of statistical significance and heterogeneity [12,13,23–26].
At the 1-month follow-up, four studies [12,23–25] reported outcomes. The pooled ef-
fect size was Hedges’s g = −0.529 (95% CI = −1.163 to 0.105; p = 0.102; I2 = 77.6%). This
indicates a moderate reduction in pain severity at 1 month with zinc supplementation;
however, the result did not reach statistical significance at the 0.05 level.
At the 2-month follow-up, three studies [12,23,25] provided data. The pooled effect
size was Hedges’s g = −1.409 (95% CI = −2.146 to −0.672; p < 0.001; I2 = 95.7%), suggesting a
large reduction in pain severity at 2 months.
At the 3-month follow-up, four studies [12,13,25,26] reported outcomes. The pooled
effect size was Hedges’s g = −1.068 (95% CI = −1.697 to −0.439; p = 0.001; I2 = 85.2%), demon-
strating a sustained large reduction in pain severity at 3 months.
To investigate the relationship between treatment duration and effect size, a meta-
regression was performed using follow-up time (in months) as a continuous moderator.
The analysis revealed a significant association between longer treatment duration and
greater reductions in pain severity (regression coefficient = −0.452 per month; p < 0.001)
Figure 5. This suggests that the efficacy of zinc supplementation increases with longer
treatment periods.
Figure 4. Forest plot for the subgroup analysis using the follow-up duration as the moderator,
including one, two, and three months. The directions of association between zinc supplementation
and pain scale assessment were consistent across all follow-up durations, with overlapping 95%
confidence intervals (CIs), indicating similar trends in pain reduction over time despite varying levels
of statistical significance and heterogeneity [12,13,23–26].
At the 1-month follow-up, four studies [
12
,
23
–
25
] reported outcomes. The pooled
effect size was Hedges’s g =
−
0.529 (95% CI =
−
1.163 to 0.105; p= 0.102; I
2
= 77.6%). This
indicates a moderate reduction in pain severity at 1 month with zinc supplementation;
however, the result did not reach statistical significance at the 0.05 level.
At the 2-month follow-up, three studies [
12
,
23
,
25
] provided data. The pooled effect
size was Hedges’s g =
−
1.409 (95% CI =
−
2.146 to
−
0.672; p< 0.001; I
2
= 95.7%), suggesting
a large reduction in pain severity at 2 months.
At the 3-month follow-up, four studies [
12
,
13
,
25
,
26
] reported outcomes. The pooled
effect size was Hedges’s g =
−
1.068 (95% CI =
−
1.697 to
−
0.439; p= 0.001; I
2
= 85.2%),
demonstrating a sustained large reduction in pain severity at 3 months.
To investigate the relationship between treatment duration and effect size, a meta-
regression was performed using follow-up time (in months) as a continuous moderator.
The analysis revealed a significant association between longer treatment duration and
greater reductions in pain severity (regression coefficient =
−
0.452 per month; p< 0.001)
Nutrients 2024,16, 4116 9 of 17
Figure 5. This suggests that the efficacy of zinc supplementation increases with longer
treatment periods.
Nutrients 2024, 16, 4116 8 of 16
Figure 5. Meta-regression of Hedges’s g versus treatment duration (month). The coefficient was -
0.452 with a p value < 0.001.
We also conducted a meta-regression to examine the impact of zinc dosage (milli-
grams per day) on pain reduction. To ensure accurate dosing comparisons, we converted
all zinc supplement dosages to elemental zinc based on their specific compositions, refer-
encing Saper et al. (2009) [27], which states that zinc gluconate contains 14.3% elemental
zinc and zinc sulfate contains 23% elemental zinc. The analysis indicated a significant
dose–response relationship, with higher daily doses of zinc associated with greater reduc-
tions in pain severity (regression coefficient = −0.02 per milligrams; p = 0.005) Figure 6.
This finding implies that both the duration and dosage of zinc supplementation contribute
to its effectiveness in alleviating menstrual pain.
Figure 6. Meta-regression of Hedges’s g against daily dose (mg/day). Coefficient = −0.02; p = 0.005.
Figure 5. Meta-regression of Hedges’s g versus treatment duration (month). The coefficient was
−0.452 with a pvalue < 0.001.
We also conducted a meta-regression to examine the impact of zinc dosage (milligrams
per day) on pain reduction. To ensure accurate dosing comparisons, we converted all zinc
supplement dosages to elemental zinc based on their specific compositions, referencing
Saper et al. (2009) [
27
], which states that zinc gluconate contains 14.3% elemental zinc
and zinc sulfate contains 23% elemental zinc. The analysis indicated a significant dose–
response relationship, with higher daily doses of zinc associated with greater reductions
in pain severity (regression coefficient =
−
0.02 per milligrams; p= 0.005) Figure 6. This
finding implies that both the duration and dosage of zinc supplementation contribute to its
effectiveness in alleviating menstrual pain.
Nutrients 2024, 16, 4116 8 of 16
Figure 5. Meta-regression of Hedges’s g versus treatment duration (month). The coefficient was -
0.452 with a p value < 0.001.
We also conducted a meta-regression to examine the impact of zinc dosage (milli-
grams per day) on pain reduction. To ensure accurate dosing comparisons, we converted
all zinc supplement dosages to elemental zinc based on their specific compositions, refer-
encing Saper et al. (2009) [27], which states that zinc gluconate contains 14.3% elemental
zinc and zinc sulfate contains 23% elemental zinc. The analysis indicated a significant
dose–response relationship, with higher daily doses of zinc associated with greater reduc-
tions in pain severity (regression coefficient = −0.02 per milligrams; p = 0.005) Figure 6.
This finding implies that both the duration and dosage of zinc supplementation contribute
to its effectiveness in alleviating menstrual pain.
Figure 6. Meta-regression of Hedges’s g against daily dose (mg/day). Coefficient = −0.02; p = 0.005.
Figure 6. Meta-regression of Hedges’s g against daily dose (mg/day). Coefficient =
−
0.02; p= 0.005.
Nutrients 2024,16, 4116 10 of 17
To assess the robustness of our findings and further explore heterogeneity, sensitivity
analysis was undertaken through the one-study removal method Figure 7. Excluding
Kashefi et al. (2014) [
23
], which had the largest effect size and contributed substantially to
heterogeneity, reduced the I
2
value to 92.2% and yielded a pooled effect size of Hedges’s
g = −1.286
(95% CI =
−
1.943 to
−
0.629; p< 0.001). This indicates that while heterogene-
ity decreased, the overall significant effect of zinc supplementation on pain reduction
remained consistent.
Nutrients 2024, 16, 4116 9 of 16
To assess the robustness of our findings and further explore heterogeneity, sensitivity
analysis was undertaken through the one-study removal method Figure 7. Excluding Ka-
shefi et al. (2014) [23], which had the largest effect size and contributed substantially to
heterogeneity, reduced the I2 value to 92.2% and yielded a pooled effect size of Hedges’s
g = −1.286 (95% CI = −1.943 to −0.629; p < 0.001). This indicates that while heterogeneity
decreased, the overall significant effect of zinc supplementation on pain reduction re-
mained consistent.
Figure 7. Sensitivity analysis using the one-study removal method. The primary outcome remained
consistent after excluding each individual trial. Zinc supplementation consistently showed signifi-
cant pain reduction [12,13,23–26].
To evaluate the potential for publication bias, a funnel plot of effect sizes versus
standard errors was created Figure 8. Visual assessment revealed asymmetry, suggesting
potential publication bias.
Figure 8. Funnel plot of included studies displaying asymmetrical distribution, suggesting potential
publication bias.
3.4. Secondary Outcome: Treatment-Associated Adverse Events
The incidence of treatment-associated adverse events was low across the included
studies. Only 11 participants reported mild side effects, such as gastrointestinal discom-
fort and nausea [12,13,23]. The meta-analysis of adverse event rates showed no statistically
significant difference between the zinc supplementation group and the placebo group (odds
ratio [OR] = 2.536; 95% CI = 0.78 to 8.26; p = 0.122; I2 = 0%) Figure 9. This suggests that zinc
supplementation is generally well-tolerated among women with primary dysmenorrhea.
Figure 7. Sensitivity analysis using the one-study removal method. The primary outcome remained
consistent after excluding each individual trial. Zinc supplementation consistently showed significant
pain reduction [12,13,23–26].
To evaluate the potential for publication bias, a funnel plot of effect sizes versus
standard errors was created Figure 8. Visual assessment revealed asymmetry, suggesting
potential publication bias.
Nutrients 2024, 16, 4116 9 of 16
To assess the robustness of our findings and further explore heterogeneity, sensitivity
analysis was undertaken through the one-study removal method Figure 7. Excluding Ka-
shefi et al. (2014) [23], which had the largest effect size and contributed substantially to
heterogeneity, reduced the I2 value to 92.2% and yielded a pooled effect size of Hedges’s
g = −1.286 (95% CI = −1.943 to −0.629; p < 0.001). This indicates that while heterogeneity
decreased, the overall significant effect of zinc supplementation on pain reduction re-
mained consistent.
Figure 7. Sensitivity analysis using the one-study removal method. The primary outcome remained
consistent after excluding each individual trial. Zinc supplementation consistently showed signifi-
cant pain reduction [12,13,23–26].
To evaluate the potential for publication bias, a funnel plot of effect sizes versus
standard errors was created Figure 8. Visual assessment revealed asymmetry, suggesting
potential publication bias.
Figure 8. Funnel plot of included studies displaying asymmetrical distribution, suggesting potential
publication bias.
3.4. Secondary Outcome: Treatment-Associated Adverse Events
The incidence of treatment-associated adverse events was low across the included
studies. Only 11 participants reported mild side effects, such as gastrointestinal discom-
fort and nausea [12,13,23]. The meta-analysis of adverse event rates showed no statistically
significant difference between the zinc supplementation group and the placebo group (odds
ratio [OR] = 2.536; 95% CI = 0.78 to 8.26; p = 0.122; I2 = 0%) Figure 9. This suggests that zinc
supplementation is generally well-tolerated among women with primary dysmenorrhea.
Figure 8. Funnel plot of included studies displaying asymmetrical distribution, suggesting potential
publication bias.
3.4. Secondary Outcome: Treatment-Associated Adverse Events
The incidence of treatment-associated adverse events was low across the included
studies. Only 11 participants reported mild side effects, such as gastrointestinal discomfort
and nausea [
12
,
13
,
23
]. The meta-analysis of adverse event rates showed no statistically
significant difference between the zinc supplementation group and the placebo group (odds
ratio [OR] = 2.536; 95% CI = 0.78 to 8.26; p= 0.122; I
2
= 0%) Figure 9. This suggests that zinc
supplementation is generally well-tolerated among women with primary dysmenorrhea.
Nutrients 2024,16, 4116 11 of 17
Nutrients 2024, 16, 4116 10 of 16
Figure 9. Forest plot of adverse event rates associated with treatment. No significant difference was
observed between the two groups (p = 0.122) [12,13,23].
4. Discussion
4.1. Summary of Findings
In this meta-analysis, zinc supplementation was shown to significantly reduce pain
severity in women with primary dysmenorrhea, and this statistical significance was main-
tained in sensitivity analyses. We found that lower doses of zinc were sufficient to achieve
therapeutic outcomes without increasing the risk of adverse events. Moreover, longer du-
rations of zinc supplementation correlated with greater reductions in pain severity. To our
understanding, this study is the first systematic review and meta-analysis to quantify the
effect of zinc on primary dysmenorrhea.
4.2. Mechanisms of Zinc in Dysmenorrhea
The pathogenesis of primary dysmenorrhea is closely linked to elevated levels of
prostaglandins and leukotrienes. Studies have demonstrated that women experiencing
painful menstruation exhibit higher concentrations of PGF2-alpha and leukotrienes in
their menstrual blood and uterine tissues [2,5,28]. These mediators induce strong uterine
contractions, which temporarily reduce or halt blood flow to the uterus, leading to oxygen
deprivation, muscle spasms, and resultant pain [29]. Furthermore, ischemia–reperfusion
injury contributes to dysmenorrhea, as the restoration of blood flow generates reactive
oxygen species (ROS) that cause tissue damage and exacerbate pain. Consequently, the
presence of these free oxygen radicals likely intensifies the discomfort associated with
dysmenorrhea [30].
Zinc supplementation may alleviate these symptoms through multiple mechanisms.
Primarily, zinc reduces prostaglandin synthesis via its antioxidant and anti-inflammatory
effects, thereby improving microcirculation in the endometrium [10,31–33]. Enhanced
uterine circulation can mitigate ischemia and reperfusion injury, subsequently decreasing
the release of ROS that cause tissue damage and pain [11,30]. In vivo studies have indi-
cated that zinc decreases the activity of cyclooxygenase-2 (COX-2), a key enzyme involved
in prostaglandin production [32,34]. Additionally, zinc may prevent uterine spasms and
pain by modulating oxidative stress and inflammatory responses, potentially through the
upregulation of superoxide dismutase 1 (SOD1) and the reduction of inflammatory cyto-
kines [35,36].
The presence of copper–zinc superoxide dismutase in uterine tissue further supports
zinc’s role in enhancing antioxidant defenses, which may alleviate cramping and pain
[37]. Moreover, lower zinc levels have been observed in women with premenstrual syn-
drome during the luteal phase compared to controls, suggesting a potential zinc defi-
ciency [38]. This deficiency may contribute to the increased severity of dysmenorrhea
symptoms, highlighting the importance of adequate zinc supplementation.
Figure 9. Forest plot of adverse event rates associated with treatment. No significant difference was
observed between the two groups (p= 0.122) [12,13,23].
4. Discussion
4.1. Summary of Findings
In this meta-analysis, zinc supplementation was shown to significantly reduce pain
severity in women with primary dysmenorrhea, and this statistical significance was main-
tained in sensitivity analyses. We found that lower doses of zinc were sufficient to achieve
therapeutic outcomes without increasing the risk of adverse events. Moreover, longer
durations of zinc supplementation correlated with greater reductions in pain severity. To
our understanding, this study is the first systematic review and meta-analysis to quantify
the effect of zinc on primary dysmenorrhea.
4.2. Mechanisms of Zinc in Dysmenorrhea
The pathogenesis of primary dysmenorrhea is closely linked to elevated levels of
prostaglandins and leukotrienes. Studies have demonstrated that women experiencing
painful menstruation exhibit higher concentrations of PGF2-alpha and leukotrienes in
their menstrual blood and uterine tissues [
2
,
5
,
28
]. These mediators induce strong uterine
contractions, which temporarily reduce or halt blood flow to the uterus, leading to oxygen
deprivation, muscle spasms, and resultant pain [
29
]. Furthermore, ischemia–reperfusion
injury contributes to dysmenorrhea, as the restoration of blood flow generates reactive
oxygen species (ROS) that cause tissue damage and exacerbate pain. Consequently, the
presence of these free oxygen radicals likely intensifies the discomfort associated with
dysmenorrhea [30].
Zinc supplementation may alleviate these symptoms through multiple mechanisms.
Primarily, zinc reduces prostaglandin synthesis via its antioxidant and anti-inflammatory
effects, thereby improving microcirculation in the endometrium [
10
,
31
–
33
]. Enhanced
uterine circulation can mitigate ischemia and reperfusion injury, subsequently decreasing
the release of ROS that cause tissue damage and pain [
11
,
30
].
In vivo
studies have indicated
that zinc decreases the activity of cyclooxygenase-2 (COX-2), a key enzyme involved in
prostaglandin production [
32
,
34
]. Additionally, zinc may prevent uterine spasms and
pain by modulating oxidative stress and inflammatory responses, potentially through
the upregulation of superoxide dismutase 1 (SOD1) and the reduction of inflammatory
cytokines [35,36].
The presence of copper–zinc superoxide dismutase in uterine tissue further supports
zinc’s role in enhancing antioxidant defenses, which may alleviate cramping and pain [
37
].
Moreover, lower zinc levels have been observed in women with premenstrual syndrome
during the luteal phase compared to controls, suggesting a potential zinc deficiency [
38
].
This deficiency may contribute to the increased severity of dysmenorrhea symptoms,
highlighting the importance of adequate zinc supplementation.
4.3. Clinical Evidence Supporting Zinc’s Therapeutic Effects
Recent clinical studies have further supported the therapeutic effects of zinc on
menstrual-related symptoms. Jafari et al. (2020) [
39
] performed a randomized, double-
blind, placebo-controlled trial and revealed that zinc supplementation significantly reduced
Nutrients 2024,16, 4116 12 of 17
physical and psychological symptoms in young women with premenstrual syndrome
(PMS) by decreasing biomarkers of inflammation and oxidative stress. Similarly, Ahmadi
et al. (2023) [
40
] reported that zinc supplementation resulted in significant improvements in
PMS symptoms among female university students, highlighting zinc’s role in modulating
inflammatory responses. Additionally, Oboza et al. (2024) [
41
] explored the relationships
between PMS and dietary factors, finding that zinc consumption correlated with a decrease
in PMS symptoms, which suggests a potential link between zinc intake and menstrual pain
relief. However, previous reviews did not quantify the analgesic effect of zinc specifically
on menstrual pain. Our meta-analysis addresses this gap by providing a quantitative
assessment of zinc’s impact on pain severity in dysmenorrhea, offering more definitive
evidence of its effectiveness as an analgesic agent in this context.
4.4. Other Nutrients in Managing Dysmenorrhea
In addition to zinc, several other nutrients have shown promising results in manag-
ing dysmenorrhea and other inflammatory conditions. Studies indicate that vitamin D
can reduce the severity of menstrual pain by decreasing the synthesis of prostaglandins,
which are key mediators of pain and inflammation [
42
–
44
]. Furthermore, calcium has
been shown to reduce muscle contractions, which can alleviate the intensity of men-
strual cramps [
42
,
43
,
45
,
46
]. Recent findings suggest that curcumin, a polyphenol found in
turmeric, demonstrates significant anti-inflammatory effects by suppressing the synthesis
of prostaglandins [
47
], thereby helping to reduce menstrual pain [
48
–
50
]. In a randomized
controlled trial by Talebpour et al. (2023) [
51
], curcumin supplementation significantly
decreased high-sensitivity C-reactive protein (hsCRP), an inflammatory biomarker, without
affecting iron metabolism in healthy women with PMS and dysmenorrhea. Based on the
above evidence, curcumin may reduce the severity of dysmenorrhea and premenstrual
syndrome (PMS) symptoms.
Zinc, vitamin D, and curcumin all reduce prostaglandin synthesis through anti-
inflammatory processes, thereby decreasing pain severity. In contrast, calcium alleviates
menstrual pain by directly reducing uterine muscle contractions, representing a differ-
ent pathway to pain relief. Consistent with previous reviews, vitamin D supplementa-
tion typically requires approximately two months to manifest positive effects [
42
,
52
,
53
],
aligning with our study’s findings of significant symptom relief after an eight-week
intervention period.
However, there is insufficient research in the literature to directly compare the effects
of these nutrients with zinc on primary dysmenorrhea or to comprehensively assess their
combined effects and side-effect profiles. While the concurrent use of these nutrients
may offer enhanced efficacy in alleviating pain and improving overall well-being, further
research is necessary to confirm their synergistic benefits and to evaluate the potential for
increased adverse effects, such as gastrointestinal disturbances.
It is possible that combining zinc and calcium could provide additional therapeutic
benefits due to their distinct mechanisms of action. Nonetheless, clinical trials are required
to establish their efficacy and safety when used together.
The combined use of these nutrients may be more effective than using them individu-
ally in alleviating pain and improving overall well-being. Future research should explore
their synergistic effects to provide a comprehensive, non-pharmacological approach to
managing dysmenorrhea and similar inflammatory conditions.
4.5. Addressing High Heterogeniety in the Meta-Analysis
While our findings on zinc supplementation offer insight into a potential non- phar-
macological option for managing primary dysmenorrhea, the high level of heterogeneity
(I
2
= 94.31%) among included studies warrants careful consideration. This substantial
variability likely stems from differences in study protocols, including variations in zinc
formulations, dosages, and treatment durations, which may affect the overall effectiveness
of zinc in pain reduction. For example, the study by Kashefi et al. (2014) [
23
] used a
Nutrients 2024,16, 4116 13 of 17
considerably higher dose of zinc sulfate, while the study by Safdar et al. (2022) [
13
] utilized
a different form of supplement—zinc gluconate at a lower dose—to the other five studies,
which used zinc sulfate and included extended follow-up periods of 3 to 6 months. These
factors contribute to the observed heterogeneity, underscoring the need for a cautious
interpretation of our pooled results and suggesting that standardized approaches in future
studies would be beneficial.
Given these differences, we conducted further analyses to explore the specific effects
of zinc dosage and treatment duration on its efficacy, aiming to clarify how these factors
influence outcomes and to provide a more comprehensive understanding of zinc’s role in
alleviating primary dysmenorrhea.
4.6. Impact of Zinc Dosage and Treatment Duration
In our subgroup analysis based on follow-up duration,