Treatments in Periorbital Hyperpigmentation: A Systematic Review and Single-Arm Meta- Analysis of Clinical Trials

Treatments in Periorbital Hyperpigmentation: A Systematic Review and Single-Arm Meta- Analysis of Clinical Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Treatments in Periorbital Hyperpigmentation: A Systematic Review and Single-Arm Meta- Analysis of Clinical Trials Salma Beltran Covarrubias, Angelo Magallanes Bajana, España De la Rosa Valdez, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7537721/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 18 You are reading this latest preprint version Abstract Background: Periorbital hyperpigmentation (POH) is a common cosmetic concern characterized by bilateral darkening around the eyes, impacting quality of life. Classified as pigmented, vascular, and structural. Treatments include non-invasive treatments encompass topical agents and lasers, while invasive options include fillers or surgery. Despite a standardized guideline, this study synthesizes current evidence to identify the most effective therapies, evidence-based strategies for optimal POH management. Methods: Following PRISMA guidelines and registering this review in PROSPERO (CRD420251082683), six databases were searched through June 2025 including randomized controlled trials of periorbital hyperpigmentation therapies. Primary outcomes include dermatologist assessments, pigmentation grading scales, patient-reported satisfaction and studies reporting response categories (e.g., excellent or good). Secondary outcomes will include adverse events as erythema. Random-effects models were used to calculate pooled effect sizes. Risk of bias was assessed using the Cochrane Rob 2.0 tool for randomized controlled trials (RCTs) and the ROBINS-I V2 tool for non-randomized controlled trials. Results: Thirty-one studies (n = 1,257) met inclusion criteria. Clinical improvement was assessed by dermatologist evaluation as “good” (>50%) and “excellent” (>75%). Carboxytherapy achieved the highest pooled rate of good improvement 0.50 (95% CI: 0.27 to 0.73; I² = 74.8%), and of excellent improvement 0.26 (95% CI: 0.17 to 0.37; I² = 15.3%). Carboxytherapy also was associated with notable reductions in VAS scores (4.69; 95% CI: 3.97 to 5.40; I² = 67.4%), melanin index reduction (75.23; 95% CI: 23.41 to 127.04; I² = 97.7%) and the lowest pooled value for erythema index (41.09 (95% CI: 28.58 to 53.60). For patient satisfaction carboxytherapy consistently yielded the highest rate of good satisfaction (0.52; 95% CI: 0.38–0.66; I² = 32.8%), whereas carboxytherapy (0.21, 95% CI: 0.07 to 0.47; I² = 56.4%) and PRP consistently achieved an excellent satisfaction (0.18; 95% CI: 0.11–0.28; I² = 0.00%). Conclusion: Carboxytherapy and PRP improve clinical efficacy and patient satisfaction in POH by effectively reducing pigmentation and erythema with favorable safety profiles. However, study heterogeneity and lack of standardized subtype classifications limit conclusions. Well-designed, standardized trials are essential to optimize treatment protocols and confirm the long-term safety. VAS scores Periorbital hyperpigmentation Carboxytherapy Platelet-rich plasma (PRP) Pigmentation Erythema Patient satisfaction Figures Figure 1 Figure 2 Figure 3 1. Introduction Periorbital hyperpigmentation (POH) is a common dermatological condition, characterized by bilateral darkening around the eyes, sometimes spreading to adjacent facial areas. Although considered a cosmetic concern, POH can negatively affect emotional well-being and quality of life (QOL)[ 1 ]. Despite its frequency, data remains limited. An Indian study reported a 30.8% prevalence, predominantly among individuals aged 16 to 25 years[ 2 ], [ 3 ]. POH is classified into pigmented, vascular, and structural which is associated with post-inflammatory hyperpigmentation (PIH)[ 4 ], [ 5 ], [ 6 ]. Accurate subtype determination is essential for guiding personalized treatment strategies. Multiple therapeutic options can be employed for POH, with topical agents commonly used as first-line therapy. Hydroquinone, a widely used depigmenting agent and kojic acid interfering with melanogenesis [ 7 ]. For refractory or severe POH, laser therapy offers a viable treatment option [ 6 ]. Structural POH can be addressed with fillers, common filler material options include hyaluronic acid, calcium hydroxyapatite, and autologous fat grafts; the latter is especially beneficial for lower eyelid skin and increased vascular visibility or prominent orbicularis oculi muscle[ 6 ]. However, they are not a replacement for surgical correction in cases of significant orbital fat prolapse. In such cases, blepharoplasty remains an effective surgical intervention for hyperpigmentation caused by fat deposits or excess skin[ 3 ]. Although some treatments demonstrate benefits in particular cases, no consensus exists on the optimal approach to managing overall POH, reinforcing the importance of additional comparative research. Although POH is a common dermatologic condition with cosmetic and psychosocial implications, the management remains limited, and no standardized treatment guidelines exist. This study provides a comprehensive and up-to-date synthesis of current therapies using meta-analytic methods to assess and compare their effectiveness. By identifying the most effective strategies, we aim to support evidence-based clinical decision-making and address the psychosocial and emotional burden associated with POH. 2. Methodology The present systematic review followed the recommendations and criteria established by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines[ 8 ]. We pre-registered the protocol at the International Prospective Register of Systematic Review (PROSPERO) with the identifier code CRD420251082683[ 9 ] . 2.1. Eligibility criteria: Type of study, participants, and intervention We conducted a systematic review and meta-analysis of relevant studies published from the inception of the database to the present, including only randomized clinical trials (RCTs) and cross over studies, in English and Spanish. Studies were excluded if they were duplicates or if the necessary data could not be obtained, or a response from the original author could not be received. This study included participants of all ages undergoing any type of treatment for periorbital hyperpigmentation. Eligible interventions may include, but are not limited to, platelet-rich plasma (PRP), chemical peels, topical depigmenting agents (e.g., hydroquinone, kojic acid), lasers, fillers, autologous fat grafting, baric oxygen, among others. Only studies that evaluated any of these interventions, compared directly with standard care, placebo, or other interventions, were included. 2.1.1. Outcomes Primary outcomes will include clinical improvement in periorbital hyperpigmentation, measured by blinded photographic assessments, pigmentation grading scales, colorimetric analysis, and patient-reported satisfaction (e.g., VAS or global ratings). Studies reporting response categories (e.g., excellent, good, none) or changes in skin thickness and density will also be included. Secondary outcomes will include adverse events (e.g., pain, bruising, edema, itching, erythema), and changes in quality of life (e.g., DLQI). Studies must report at least one predefined outcome to be eligible. 2.1.2. Searching methods We initially conducted a systematic search on June 26th, 2025, on PubMed/MEDLINE, Cochrane, Scopus, Web of Science, EMBASE, CINAHL and Google Scholar using the following terms: of “periorbital hyperpigmentation”, “dark circles”, “infraorbital pigmentation”, and various therapeutic interventions such as “lasers”, “chemical peels”, “fillers”, “platelet-rich plasma”, “topical depigmenting agents”, among others. We have provided all detailed search strategies in the supplementary material (Supplementary Tables 1–7). 2.1.3. Selection of studies We exported all references to Rayyan (Rayyan Systems Inc., Cambridge, MA, USA) and removed duplicates[ 10 ].Two authors independently (A.C.L. and M.V.S.) completed the eligibility assessment, first by title and abstract analysis and, subsequently, by full-text assessment. In disagreements between reviewers, a third reviewer (Y.C.C.) helped reach a consensus. 2.1.4. Data extraction Two independent reviewers extracted the data (E.M.C. and Y.C.C.), resolving disagreements through consensus.. In cases of multiple overlapping reports from the same study, we included the report with the most relevant information or the earliest publication date. Extracted data included sample sizes, intervention types, and measured outcomes. We employed conventional data extraction methods, complemented by specialized tools such as WebPlotDigitizer (Automeris, Austin, TX, USA) for digitizing data from graphs, Cochrane Calculator for statistical conversions, and StatsToDo for advanced calculations[ 11 ], [ 12 ], [ 13 ]. These outcomes comprised clinical improvement in periorbital hyperpigmentation, measured by blinded photographic assessments, pigmentation grading scales, colorimetric analysis, patient-reported satisfaction (e.g., VAS or global ratings) and response categories (e.g., excellent, good, none) or changes in skin thickness. Additional extracted data included subgroup characteristics, such as country of study, risk of bias levels, and study design. 2.1.5. Assessment of risk of bias in included studies To assess the quality of the studies included in the systematic review, according to the Cochrane guidelines we applied the Cochrane RoB 2.0 tool for randomized controlled trials (RCTs)[ 14 ] and the ROBINS-I V2 tool for non-randomized controlled trials[ 15 ]. Two independent reviewers (A.C.L and M.V.S) evaluated the risk of bias in each study, considering the specific criteria and guidelines provided by the respective tools. We resolved discrepancies between reviewers through discussion with a third, blinded reviewer (S.A.B.). 2.1.6. Statistical analysis A meta-analysis was performed using R version 3.4.3[ 16 ], [ 17 ]. The pooled effect of the outcomes was examined using a random-effects meta-analysis (DerSimonian-Laird approach)[ 18 ]. Whenever the number of studies reporting an outcome of interest was insufficient, only a qualitative analysis of the results was performed. Effect sizes were expressed as Relative Risk (RR), Mean difference (MD), proportions or standardized mean difference (SMD) and 95% CI. The I² statistic assessed heterogeneity, and the following cut-off values used for interpretation: 50% were considered small, medium, and large heterogeneity respectively[ 19 ]. We initially planned to conduct a network meta-analysis (NMA) to compare the relative effectiveness of the included interventions. However, during data extraction, we found that the network was disconnected, with many interventions lacking a shared comparator. This prevented construction of a coherent network. Consequently, we performed single-arm meta-analyses for each intervention separately, without direct or indirect comparisons between treatments. As originally planned, sensitivity analyses according to the leave-one-out method were performed to determine the influence of individual studies on the overall effect, using diagnostic plots proposed by Viechtbauer and Cheung[ 20 ]. Egger's regression test examined publication bias when ten or more reports with the same outcome were available[ 21 ]. 3. Results 3.1 Study selection Originally, we identified 1384 potential articles across seven databases. After removing 802 duplicate articles, we conducted a screening based on title and abstract, leading to the exclusion of 500 articles. We sought 82 articles for full-text retrieval and eligibility assessment, of which 52 were excluded. A total of 31 studies were included in this review. Additionally, 1 study identified through previous reviews were included, resulting in a total of 31 studies in this review. We summarized this process in our PRISMA flow diagram (Fig. 1 ). 3.2 Characteristics of included studies We analyzed 31 RCTs compromising 1,257 patients across eight countries. Most studies originated from Iran (35%) and Egypt (29%), followed by China (10%), India (10%) and the United States (7%); smaller contributions came from Japan, Pakistan and Thailand (3% each). Melanin Index was assessed in 8 of the 31 studies, 16.13% reported statistically significant improvements with carboxytherapy, placebo, andographins, artemisinin, laser monotherapy, laser combined with placebo and PRP combined with laser; 9.68% showed no effect and 74.19% of studies did not report this outcome. Erythema Index was evaluated in 5 studies with statistically significant improvement observed in 6.45% of studies with artemisinin, carboxytherapy and placebo. Conversely 9.68% showed no statistical difference and 83.87% didn’t report this outcome. Improvement of ≥ 50% by physician assessment was reported in 15 studies where 12.90% demonstrated significant improvement with carboxytherapy, placebo, PRP, TCA combined with lactic acid peeling and plasma gel injection; 35.48% found no significant results and 51.61% of studies did not report this outcome. ≥75% improvement was assessed in 18 studies. From which 16% showed a significant trend favoring carboxytherapy, CO2 laser, placebo, PRP, TCA plus Lactic acid peeling and plasma gel injection, 42% of studies found no significant difference and 42% did not include this outcome. VAS outcomes were reported in 6 studies. Of these 16.12% reported significant benefit from interventions including carboxytherapy, laser (alone or with placebo), PRP alone and combined with laser and plasma gel injections. One study (3.22%) found no significant difference and 80.65% of studies did not include this outcome. A good and excellent patient satisfaction was evaluated in 16 studies, from which 29% reported statistically significant patient satisfaction with PRP alone, carboxytherapy, PRP combined with laser, laser combined with placebo, fat injection alone and with combination therapy, TCA combined with lactic acid peel, Andrographis, placebo, microneedling combined with TCA and CO2 laser; 22.58% found no effet and 48.38% of articles did not report these outcomes. PRP and carboxytherapy were the most frequently reported and consistently demonstrated improvement across multiple outcomes, highlighting their role as therapeutic options. We summarized this information in (Table 1 )22–52. Table 1 General outcome of included studies Author and Year Country Study design Types of Interventions Sample size per intervention Follow up (weeks) Key points Afzal N, et al., 2024 [ 22 ] USA RCT THDA + AZ and THDA alone 44 8 THDA and AZ significantly improved pigmentation, and redness, while THDA alone worsened wrinkles and erythema. Ahmadraji F, et al., 2015 [ 23 ] Iran RCT-Split face Emu oil + Vitamin k + Caffeine Pad And Placebo 11 4 The Emu oil + vitamin K + caffeine treatment improved elasticity and decreased in dark circles. In contrast, the placebo showed no elasticity improvement, and worsened pigmentation. Ahmed N, et al., 2019 [ 24 ] Egypt RCT Carboxytherapy, TCA + LA Peeling And Vitamin C 45 5 Carboxytherapy, chemical peeling, and vitamin C mesotherapy all effectively reduced periorbital pigmentation, though mesotherapy was less tolerable. Asilian A, et al., 2021 [ 25 ] Iran RCT-Split face Carboxytherapy and PRP 21 8 The study concluded that both PRP and carboxytherapy resulted in insignificant changes. Assaf, et al., 2022 [ 26 ] Egypt RCT - Split face Carboxytherapy and Microneedling with topical Glutathione 31 13 Carboxytherapy showed significantly greater VAS improvement and higher patient satisfaction than microneedling with glutathione during both treatment and follow-up. Behrangi E, et al., 2022 [ 27 ] Iran RCT Fractional CO2 laser therapy and Fractional CO2 laser + PRP treatments 100 26 Adding PRP to CO₂ laser reduced periorbital hyperpigmentation by 25% with erythema resolving faster. Budania A, et al., 2020 [ 28 ] India RCT - Split face Novel PRP and Conventional PRP 21 13 Both novel and conventional PRP significantly improved DLQI and reduced VAS scores from baseline. Dayal S, et al., 2019 [ 29 ] India RCT 20% glycolic acid peeling, 15% lactic acid peeling and 12% ferulic acid peeling 90 13 All three peels significantly reduced under-eye hyperpigmentation, with glycolic acid showing the greatest improvement over lactic and ferulic acid. Diab H., et al., 2021 [ 30 ] Egypt Split face PRP and Plasma gel 40 16 PRP and plasma gel were both effective for periorbital rejuvenation, with plasma gel showing better improvement. However, neither significantly reduced melanin concentration. Both treatments were well tolerated. El-Tahlawi S, et al., 2022 [ 31 ] Egypt Split face PRP injections and Carboxytherapy 23 16 The study concluded that PRP was more effective and tolerable than carboxytherapy for treating periorbital dark circles; both treatments had high patient and doctor satisfaction, with no significant difference in pain during the procedure. Ellabban, et al., 2019 [ 32 ] Egypt RCT Peeling agent: TCA 3.75% + LA 15% and Autologous PRP injections 42 6 Chemical peeling showed significantly better results than PRP, reporting good improvement and most were very pleased to be extremely satisfied. Fabi S, et al., 2023 [ 33 ] USA RCT VYC-15L and Placebo 135 52 At 3- and 12-month post-treatment, most VYC-15L patients were satisfied, not bothered by dark circles, and would recommend the treatment. Ghandehari, et al., 2020 [ 34 ] Iran Clinical trial - Split face Tranexamic acid + CO2 Laser and Tranexamic acid + Microneedling 30 13 The laser-treated side showed significantly greater improvement in infraorbital hyperpigmentation by day 60. By day 150, both sides showed similar improvement. Hamdi H, et al., 2022 [ 35 ] Iran RCT Artemisia extract eye cream and placebo eye cream 60 8.6 The Artemisia absinthium eye cream group showed greater improvements than placebo, with larger reductions in color difference, erythema and melanin, as well as a greater increase in lightness. Iranmanesh, et al., 2024 [ 36 ] Iran RCT - Split Site Intradermal injection of PRP and Intradermal injection of tranexamic acid + Vitamin C 18 13 PRP favored for showing higher satisfaction score. Kadry A, et al., 2023 [ 37 ] Egypt RCT PRP and Autologous Fat 30 24 Autologous fat treatment was significantly more effective than PRP in improving periorbital hyperpigmentation. Khan I, et al., 2023 [ 38 ] Pakistan RCT PRP and carboxytherapy 50 12 PRP had more excellent responders but higher pain scores than carboxytherapy. Lu Y, et al., 2024 [ 39 ] China RCT PRP injection after Q-switched ruby laser treatment and Q-switched ruby laser only 30 36 The combined PRP + Q-switched ruby laser treatment showed greater and longer-lasting improvements in hyperpigmentation, and patient satisfaction compared to laser alone. Nilforoushzadeh M, et al., 2020 [ 40 ] Iran Split face Fractional Er: YAG laser treatment + PRP and Fractional Er: YAG laser treatment 32 24 Fractional Er:YAG laser with PRP significantly reduced melanin index and VAS scores, while the laser alone only improved VAS scores. Nilforoushzadeh M, et al., 2021 [ 41 ] Iran RCT carboxytherapy and Q-switched Nd:YAG laser. 28 13 Both treatments significantly reduced melanin index and improved VAS scores, but carboxytherapy showed greater VAS improvement than Q-switched Nd:YAG laser. Nofal E. et al., 2018 [ 42 ] Egypt RCT-Split face PRP and carboxytherapy 30 20 PRP and carboxytherapy have similar efficacy for periorbital hyperpigmentation, but PRP causes more severe, persistent side effects, while carboxytherapy has milder, transient ones and is better tolerated. Ohshima H, et al., 2009 [ 43 ] Japan Clinical trial - Split face ANa, Placebo, and AG + placebo 14 26 ANa significantly reduced EI compared to vehicles, while vitamin C and AG showed no significant difference in EI change. MI changes were not significantly different for vitamin C. Phoo Mon N, et al., 2025 [ 44 ] Thailand RCT-Split face Andrographis paniculata extract cream And Placebo cream 19 12 Andrographis paniculata cream significantly improves skin elasticity, and reduces hyperpigmentation without harmful side effects, while placebo showed no significant improvement. Ranjan R, et al., 2016 [ 45 ] India RCT 4% hydroquinone And 30% salicylic acid peel 50 13 Both hydroquinone and salicylic acid significantly improved VAS scores and reduced DLQI. Roohaninasab M, et al., 2024 [ 46 ] Iran RCT Nanofat + SVF Nanofat + PRP Nanofat + Nd:YAG laser Nanofat only 30 12 Combined nanofat injections with SVF, PRP, or 1064-nm Q-switched Nd:YAG laser significantly outperformed nanofat alone in reducing under-eye darkness. Specifically, nanofat + PRP improved complete and dermal density, while nanofat + laser enhanced color and dermal thickness. Roshdy O, et al., 2021 [ 47 ] Egypt RCT carboxytherapy 30 ml/mn and carboxytherapy 60 ml/mn 80 6 Both standard and high dose carboxytherapy significantly reduced melanin and erythema indices. Shalash A, et al., 2023 [ 48 ] Egypt RCT Bilateral injection of PRP gel, Bilateral intradermal injection of CO2 with carboxytherapy machine And Intradermal injection of vitamin C 30 8 PRP and vitamin C significantly improved PODC grading, while carboxytherapy did not; however, no significant differences were found between the three groups. Wu X, et al. , 2022 [ 49 ] China Prospective - Split face Microneedle Fractional Radiofrequency And no treatment 22 24 Microneedling improved periorbital hyperpigmentation without reducing melanin index, while placebo showed no significant effects. Yu C, et al., 2020 [ 50 ] China RCT- Split face Phenylethyl resorcinol gel + nano-microneedle, Phenylethyl resorcinol gel, Placebo gel + nano-microneedle and Placebo gel 20 16 Phenylethyl resorcinol gel, especially when combined with nano-microneedling, significantly reduced melanin index, whereas placebo and microneedling alone did not. Zaheri, et al., 2022 [ 51 ] Iran RCT - Split face Sub-cutaneous or intradermal injection of pure carbon dioxide as carboxytherapy and Fractional CO2 laser therapy 30 4 Fractional CO2 laser therapy is a better treatment with fewer side effects than carboxytherapy, but larger studies are needed to confirm this. Zamanian A, et al., 2017 [ 52 ] Iran RCT Microneedling + TCA and CO2 Laser 51 27 CO2 Laser showed higher levels of satisfaction on fifth visit and higher response to treatment. However, only in with this intervention was notice side effects such as erythema and irritation. AG : Ascorbic Acid Glucoside, ANa : Sodium Ascorbate, DLQI : Dermatology Life Quality Index, LA : Lactic Acid, PODC : presumably post-operative pain and dysfunction, SVF : Stromal Vascular Fraction, TCA : Trichloroacetic acid, YAG Laser : Yttrium Aluminum Garnet Laser and VAS : Visual Analog Scale. 3.3 Risk of bias. We evaluated the risk of bias in 27 RCTs using RoB 2.0 tool[ 14 ]. Of these, 6 studies (22%) were deemed high risk of bias, 7 (26%) had some concerns, and 14 (52%) were deemed low risk (Fig. 2 ). 4 non-randomized studies were assessed with ROBINS-I V2 tool[ 15 ], 1 study (25%) showed a moderate risk of bias and 3 studies (75%) were considered low risk (Fig. 2 A). Overall, 55% of studies were high quality, 26% moderate quality, and 19% low quality. 3.4 Meta analysis The planned network meta-analysis was not feasible because the identified studies did not form a connected network, with multiple isolated intervention nodes and no shared comparators. Consequently, single-arm meta-analyses were performed instead. 3.4.1 > 50% improvement In this meta-analysis, data were synthesized from 30 studies encompassing a total of 718 participants. The pooled proportion of successful outcomes across all interventions was 0.51 (95% CI: 0.38 to 0.65; I² = 77.4%; Fig. 2 A). The prediction interval ranged from 0.09 to 0.92. The funnel plot revealed asymmetry suggestive of potential publication bias (Fig. 3 A). Egger’s test was not performed due to the inclusion of fewer than ten studies per subgroup. Subgroup analysis by intervention type demonstrated significant differences among treatment modalities (χ²₁₇ = 87.10, p < 0.01). Carboxytherapy alone yielded a pooled proportion of 0.50 (95% CI: 0.27 to 0.73; I² = 74.8%), indicating moderate heterogeneity across included studies. In contrast, CO₂ laser demonstrated a pooled proportion of 0.68 (95% CI: 0.45 to 0.85) with no observed heterogeneity (I² = 0%). Both interventions contributed to the overall model and were associated with favorable response rates. 3.4.2 > 75% improvement In this meta-analysis, data were synthesized from 31 studies comprising a total of 646 participants. The pooled proportion of successful outcomes across all interventions was 0.24 (95% CI: 0.18 to 0.31; I² = 53.4%; Fig. 2 B). The prediction interval ranged from 0.08 to 0.52. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig. 3 B). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis by intervention type revealed statistically significant differences (χ²₁₁ = 27.48, p < 0.01). Among the interventions with multiple observations, platelet-rich plasma (PRP) demonstrated a pooled proportion of 0.27 (95% CI: 0.11 to 0.52; I² = 71.0%), indicating high variability across studies. In contrast, carboxytherapy showed a more consistent pooled effect of 0.26 (95% CI: 0.17 to 0.37; I² = 15.3%), suggesting homogeneity among included studies. Both interventions contributed substantially to the overall model and showed clinically meaningful effects, with PRP showing wider confidence intervals due to greater heterogeneity. 3.4.3 Visual Analogue scale In this meta-analysis, we included 12 studies with a combined total of 266 participants. The pooled mean VAS score across all interventions was 4.89 (95% CI: 4.22 to 5.57; I² = 95.7%; Fig. 2 C). The prediction interval ranged from 2.23 to 7.56. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig. 3 C). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis revealed significant differences in treatment efficacy (χ² 7 = 172.28, p < 0.01). PRP demonstrated a pooled VAS of 4.77 (95% CI: 3.12 to 6.43; I² = 95.8%), while carboxytherapy yielded a pooled score of 4.69 (95% CI: 3.97 to 5.40; I² = 67.4%). Both interventions showed clinically significant improvements, although substantial heterogeneity was observed, particularly within the PRP subgroup. 3.4.4 Melanin Index In this meta-analysis, we included 17 studies with a combined total of 285 participants. The pooled mean melanin index across all interventions was 165.73 (95% CI: 141.76 to 189.69; I² = 97.7%; Fig. 2 D). The prediction interval ranged from 62.47 to 268.99. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig. 3 D). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis revealed significant differences in melanin index outcomes among treatment modalities (χ² 13 = 251.41, p < 0.01). Placebo-treated groups exhibited the highest pooled melanin index at 207.91 (95% CI: 104.81 to 311.02; I² = 98.1%), while carboxytherapy showed a substantially lower pooled index of 75.23 (95% CI: 23.41 to 127.04; I² = 97.7%). Both subgroups contributed significantly to the overall model. Notably, heterogeneity was high in both groups. 3.4.5 Erythema Index In this meta-analysis, we included 11 studies with a combined total of 207 participants. The pooled mean erythema index across all interventions was 333.20 (95% CI: 240.64 to 425.76; I² = 99.5%; Fig. 2 E). The prediction interval ranged from − 29.09 to 695.49. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig. 3 E). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis revealed significant differences in erythema scores among treatment modalities (χ²₁₀ = 2014.17, p < 0.01). Platelet-rich plasma combined with laser demonstrated the highest pooled erythema index at 394.40 (95% CI: 380.92 to 407.88), while carboxytherapy high dose showed the lowest pooled value at 41.09 (95% CI: 28.58 to 53.60). Both subgroups contributed substantially to the overall model, high level of heterogeneity was observed. 3.4.6 Patient Satisfaction: Good or > 50% This meta-analysis included 36 studies with 814 participants. The pooled proportion of successful outcomes across all interventions was 0.59 (95% CI: 0.51 to 0.67; I² = 64.5%; Fig. 2 F), with a prediction interval of 0.25 to 0.86. Funnel plot asymmetry suggested potential publication bias (Fig. 3 F). Egger’s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis by intervention type revealed statistically significant differences (χ² 22 = 65.75, p < 0.01). Carboxytherapy demonstrated a pooled efficacy of 0.52 (95% CI: 0.38 to 0.66; I² = 32.8%). PRP yielded a pooled proportion of 0.43 (95% CI: 0.24 to 0.64; I² = 63.1%), reflecting moderate heterogeneity. Vitamin C achieved a pooled effect of 0.64 (95% CI: 0.11 to 0.96; I² = 0.00%) with no heterogeneity, TCA combined with lactic acid peeling showed a pooled proportion of 0.72 (95% CI: 0.00 to 1.00; I² = 76.1%), with substantial heterogeneity and imprecise confidence intervals. 3.4.7 Patient Satisfaction: Excellent or > 75% This meta-analysis included 31 studies with 684 participants. The pooled success rate was 0.24 (95% CI: 0.17 to 0.32; I² = 64.6%; Fig. 2 G), with a prediction interval od 0.05 to 0.63. Funnel plot asymmetry suggested potential publication bias (Fig. 3 G). Egger’s test was not performed due to few studies per subgroup. Subgroup analysis by intervention type revealed statistically significant differences (χ² 21 = 64.6, p < 0.01). Carboxytherapy demonstrated a pooled efficacy of 0.21 (95% CI: 0.07 to 0.47; I² = 56.4%), indicating moderate heterogeneity. PRP yielded a pooled proportion of 0.18 (95% CI: 0.11 to 0.28; I² =0.00) and TCA combined with lactic acid peeling showed a pooled proportion of 0.20 (95% CI: 0.00 to 1.00; I² = 72.5%), though the wide confidence interval and high heterogeneity suggest greater uncertainty in the estimated effect. 4. Discussion This systematic review and meta-analysis evaluate POH treatments using clinical improvement thresholds. Carboxytherapy showed a pooled proportion of 0.50 (95% CI: 0.27 to 0.73; I² = 74.8%), indicating that half of the treated patient achieved > 50% clinical improvement. CO₂ yielded a pooled proportion of 0.68 (95% CI: 0.45 to 0.85), suggesting greater efficacy with consistent results and no observed heterogeneity (I² = 0%). Similarly, trends toward > 75% improvement were observed with carboxytherapy 0.26 (95% CI: 0.17 to 0.37; I² = 15.3%) and PRP (0.27; 95% CI: 0.11 to 0.52; I² = 71.0%). These findings align with a prior meta-analysis conducted by Mohammad A. et al, who reported good (50–75%) responses with PRP and carboxytherapy, and excellent (> 75%) improvement with chemical peel and PRP, though the latter was based on a single study. VAS outcomes, improved with carboxytherapy, laser, PRP both alone and combined with laser. Subgroup analysis showed similar VAS score reductions for PRP (pooled VAS reduction of 4.77) and carboxytherapy (4.69) suggesting a decrease in pain after either treatment. The comparable magnitudes may reflect distinct but similarly effective mechanisms given that PRP promotes collagen synthesis, angiogenesis, and epidermal regeneration, whereas carboxytherapy induces transient hypoxia triggering vasodilation and neovascularization [ 54 ]. Heterogeneity, particularly for PRP likely reflects variability in preparation methods, treatment protocols, patient population and subjectivity of VAS scoring, limiting comparability. In our qualitative synthesis both carboxytherapy and laser reduced melanin index. Subgroup analysis confirmed this with placebo showing the highest pooled melanin index and carboxytherapy the lowest. However high heterogeneity suggests variability in treatment effects. Regarding erythema index, significant reduction was seen with high dose carboxytherapy achieving the lowest value pooled proportion when compared to PRP, which achieved the highest pooled proportion. The substantial heterogeneity observed may reflect differences in treatment depth, inflammatory response and procedural variables. Although Mohammad A. et al, attempted to assess erythema in a previous meta-analysis, inconsistent reporting across the included studies limited the strength of their conclusions [ 53 ]​. Patient satisfaction was evaluated; for “good” satisfaction (> 50% improvement), carboxytherapy (pooled efficacy of 0.52; low heterogeneity), PRP (pooled proportion of 0.43; moderate heterogeneity), vitamin C (pooled effect of 0.64; no heterogeneity) and TCA + lactic acid peeling (pooled proportion of 0.72; high heterogeneity). These results emphasize the subjective improvement by patients, particularly with carboxytherapy. Compared to analysis by Mohammad A., where laser therapies ranked the highest in-patient satisfaction[ 53 ]. For excellent satisfaction (> 75% improvement), carboxytherapy yield a pooled efficacy of 0.21 with moderate heterogeneity, followed by PRP (pooled proportion of 0.18) with no heterogeneity and TCA + lactic acid (pooled proportion of 0.20) which exhibited a wide confidence interval and high heterogeneity. A similar pattern was reported by Mohammad A. et al, where combination therapies, particularly laser, yielded the highest satisfaction, followed by peels, PRP, laser alone, and carboxytherapy[ 53 ]. Despite some discrepancies, our findings consistently support PRP, carboxytherapy, and chemical peels as effective options, reinforcing their relevance in clinical practice. Currently, no standard guidelines exist for POH management. Topical agents remain most common due to availability and ease of use. For stronger effects, chemical peels are employed, though outcomes vary by skin type. Laser therapies show clinical benefit and patient satisfaction, but efficacy and safety depend on patient selection and device parameters​[ 6 ], [ 54 ]. Newer non-invasive options such as PRP and carboxytherapy demonstrate promising efficacy, particularly in vascular subtypes. For structural causes, invasive approaches like fillers or blepharoplasty may be more effective. Dermoscopic subtype identification is essential for individualized care. Beyond aesthetics, POH impacts emotional well-being, underscoring the need for patient-centered treatment. Strength and limitations This review synthesizes evidence from 31 studies, including 11 not assessed in prior reviews, and is among the first to quantitatively evaluate outcomes such as melanin and erythema index. It provides new insights into treatment efficacy and adverse effects of POH therapies. However, a network meta-analysis was not feasible, as initially intended, due to insufficient direct and indirect comparisons. Heterogeneity in study design and the absence of a standardized classification for POH subtypes further limit comparability. Treatments target different etiologies (vascular, pigmentary, structural), underscoring the need for a consistent subtype classification to enable subtype-specific outcomes and head-to-head trials. Our definition of “excellent” response was revised from ≥ 90% to ≥ 75% improvement to align with most studies and maintain analytical consistency. Despite these limitations, this review strengthens the evidence base for novel non-invasive therapies, though rigorous trials with standardized subtype definitions and longer follow-up are still needed. 5. Conclusion Our meta-analysis synthesizes evidence on clinical improvement. Findings suggest carboxytherapy and PRP, alone or combined, offer favorable efficacy and safety. Despite heterogeneity, results support non-invasive therapies in POH management. Future studies should use standardized subtype classifications and monitor adverse events to strengthen evidence. This review highlights the importance of individualized, patient-centered approaches and the potential of safe treatments to address both the cosmetic and psychological burden of POH. Abbreviations POH — Periorbital hyperpigmentation PIH — Post-inflammatory hyperpigmentation QOL — Quality of life PRP — Platelet-rich plasma VAS — Visual analog scale Statements and declarations I. Funding: This research was not funded by any special agency. II. Conflict of interest: All authors declare no conflict of interest. All authors read and approved the final manuscript. III. Availability of data and materials: All the data used to perform this analysis is publicly available in the referenced articles. The rest of the material is at the author's disposition upon reasonable request. Availability of data and materials: All data used in this analysis are publicly available in the cited articles. Additional materials are available from the corresponding author upon reasonable request. IV. Ethics approval: Given that this meta-analysis utilized previously published data from studies that had already obtained ethics approval and consent to participate, no additional ethics approval or consent was required for this research. Ethics approval and consent to participate: This study is a systematic review and meta-analysis that synthesized data from publicly available studies which had already received ethics approval and participant consent. No additional ethical approval or consent was required. V. Consent to participate: Not applicable. VI. Consent for publication: All authors have provided their consent for publication. VII. Code availability: At the author's disposition upon reasonable request. VIII. Author contributions: o Ernesto Calderon Martinez: Conceptualization, literature search, data extraction, statistical analysis, project supervision and administration, writing, review and editing. o Camila Sanchez Cruz: Conceptualization, project supervision and administration, writing, review and editing. o Salma Beltran Covarrubias: Statistical analysis, writing original draft. o Alejandro Chen Liang: Writing original draft, general project tasks, visualization, data analysis. o Montserrat Villa Sanchez: Writing original draft, general project tasks, visualization, data analysis. o Yeison Cruz Castillo: Consensus reviewer in study selection, data extraction, methodology, writing original draft. o España De la Rosa Valdez: Idea validation, independently selected studies, data analysis. o Angelo Magallanes Bajana: Independently selected studies , assessment of risk of bias, data analysis. o Frances Marie Mejia: Reviewing and editing of original manuscript. o Rovin Picavia: Reviewing and editing of original manuscript. 6. Acknowledgements Not applicable. 7. Statements of Ethics Competing interests : The authors declare no competing interests. Funding: This research was conducted without any external funding. 8. Author’s contributions: S.B.C.: Statistical analysis, consensus reviewer assessment of risk of bias, writing original draft. A.M.B.: Methodology, writing original draft, data analysis. E.D.V: Idea validation, general project tasks, visualization. A.C.L.: Independently selected studies, assessment of risk of bias, writing original draft, data analysis. M.V.S.: Independently selected studies, assessment of risk of bias, methodology, writing original draft. Y.C.C.: Consensus reviewer in study selection, data extraction, methodology, writing original draft. F.M.M.: Writing & Editing, Supervision R.P.: Writing, Review and editing. C.S.C.: Project supervision, assisting with general project tasks. E.C.M.: Conceptualization, literature search, data extraction, statistical analysis, project supervision and administration, writing, review and editing. All authors read and approved the final manuscript. References Mendiratta V, Rana S, Jassi R, Chander R (May 2019) Study of causative factors and clinical patterns of periorbital pigmentation. Indian Dermatol Online J 10(3):293–295. 10.4103/idoj.IDOJ_158_18 Heidari F, Ebrahim Zadeh M, Haji Abole M, Zadeh, Namiranian N (2025) The Frequency of Periorbital Hyperpigmentation Risk Factors. J Cosmet Dermatol 24(2):1–6. 10.1111/jocd.70036 Sarkar R, Ranjan R, Garg S, Garg VK, Sonthalia S, Bansal S (2016) Periorbital hyperpigmentation: A comprehensive review. J Clin Aesthetic Dermatology 9(1):49–55 Chatterjee M, Suwal B, Malik A, Vasudevan B (2018) A study of epidemiological, etiological, and clinicopathological factors in periocular hyperpigmentation. Pigment Int 5(1):34. 10.4103/pigmentinternational.pigmentinternational_25_17 Ranu H, Thng S, Goh BK, Burger A, Goh CL (2011) Periorbital hyperpigmentation in Asians: An epidemiologic study and a proposed classification. Dermatol Surg 37(9):1297–1303. 10.1111/j.1524-4725.2011.02065.x Samaan CB, Cartee TV (2023) Treatment of Periorbital Vascularity, Erythema, and Hyperpigmentation. Clin Plast Surg 50(3):399–409. 10.1016/j.cps.2022.12.005 Wawrzyk-Bochenek I, Rahnama M, Stachura M, Wilczyński S, Wawrzyk A (2023) Evaluation of the Reduction of Skin Hyperpigmentation Changes under the Influence of a Preparation Containing Kojic Acid Using Hyperspectral Imaging—Preliminary Study. J Clin Med 12(7). 10.3390/jcm12072710 Page MJ et al The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Mar 29 2021 BMJ Publishing Group. 10.1136/bmj.n71 Accessed PROSPERO May 01, 2025. [Online]. Available: https://www.crd.york.ac.uk/prospero/ Rayyan AI-Powered Systematic Review Management Platform. Accessed: May 01, 2025. [Online]. Available: https://www.rayyan.ai/ automeris.io Computer vision assisted data extraction from charts using WebPlotDigitizer. Accessed: May 01, 2025. [Online]. Available: https://automeris.io/ RevMan Calculator | Cochrane Training. Accessed: May 01, 2025. [Online]. Available: https://training.cochrane.org/resource/revman-calculator Home Accessed: May 01, 2025. [Online]. Available: https://www.statstodo.com/index.php Revised Cochrane (2019) risk-of-bias tool for randomized trials (RoB 2) The Risk Of Bias In Non-randomized Studies-of Interventions, Version 2 (ROBINS-I V2) assessment tool (for follow-up studies), 2024. [Online]. Available: Schwarzer G, Carpenter JR, Rücker G (2015) Meta-Analysis with R. 10.1007/978-3-319-21416-0 Harrer M, Cuijpers P, Furukawa TA, Ebert DD (2021) Doing Meta-Analysis with R: A Hands-On Guide, Doing Meta-Analysis with R , Sep. 10.1201/9781003107347 Song Y, Sun F, Redline S, Wang R (2020) Random-effects meta-analysis of combined outcomes based on reconstructions of individual patient data, Res Synth Methods , vol. 11, no. 5, p. 594, Sep. 10.1002/JRSM.1406 Higgins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis, Stat Med , vol. 21, no. 11, pp. 1539–1558, Jun. 10.1002/SIM.1186 Meng Z, Wang J, Lin L, Wu C (Apr. 2024) Sensitivity analysis with iterative outlier detection for systematic reviews and meta-analyses. Stat Med 43(8):1549–1563. 10.1002/SIM.10008 Egger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Br Med J 315(7109):629–634. 10.1136/BMJ.315.7109.629 Afzal N et al (2024) Prospective randomized double-blind comparative study of topical acetyl zingerone with tetrahexyldecyl ascorbate versus tetrahexyldecyl ascorbate alone on facial photoaging. J Cosmet Dermatol 23(7):2467–2477. 10.1111/jocd.16292 Ahmadraji F, Shatalebi M (2015) Evaluation of the clinical efficacy and safety of an eye counter pad containing caffeine and vitamin K in emulsified Emu oil base. Adv Biomed Res 4(1). 10.4103/2277-9175.148292 Ahmed NA, Mohammed SS, Fatani MI (2019) Treatment of periorbital dark circles: Comparative study of carboxy therapy vs chemical peeling vs mesotherapy. J Cosmet Dermatol 18(1):169–175. 10.1111/jocd.12536 Asilian A, Amiri A, Mokhtari F, Faghihi G, Iraji F, Mozafarpoor S (2021) Platelet-rich plasma versus carboxytherapy for the treatment of periocular hyperpigmentation; which approach is superior? Dermatol Ther 34(4):0–2. 10.1111/dth.14980 Hanan AA, Assaf A, Ahmed D (2018) Efficacy and Safety of Carboxytherapy versus Combined Microneedling with Topical Glutathione in the Treatment of Patients with Periorbital Hyperpigmentation: An EvaluatorBlind, SplitFace, Controlled Pilot Clinical Trial. Indian J Dermatol 63(2):125–130. 10.4103/ijd.IJD Behrangi E et al (2022) Efficacy and safety of platelet-rich plasma for treatment of periorbital hyperpigmentation in patients receiving fractional CO2 laser: a parallel-group blinded randomized controlled clinical trial, Iranian Journal of Dermatology , vol. 25, no. 2, pp. 99–105, Jun. 10.22034/ijd.2021.235304.1142 Budania A et al (2021) Comparing novel versus conventional technique of platelet-rich plasma therapy in periorbital hyperpigmentation: A randomized prospective split-face study. J Cosmet Dermatol 20(10):3245–3252. 10.1111/jocd.14121 Dayal S, Sangal B, Sahu P (2020) Ferulic acid 12% peel: An innovative peel for constitutional type of periorbital melanosis—Comparing clinical efficacy and safety with 20% glycolic peel and 15% lactic peel. J Cosmet Dermatol 19(9):2342–2348. 10.1111/jocd.13292 Diab HM, Elhosseiny R, Bedair NI, Khorkhed AH (2022) Efficacy and safety of plasma gel versus platelet-rich plasma in periorbital rejuvenation: a comparative split-face clinical and Antera 3D camera study. Arch Dermatol Res 314(7):661–671. 10.1007/s00403-021-02270-7 El-Tahlawi SM, Fawzy MM, El Maadawi Z, Yasen SM, Aboraia NM (2022) Platelet-rich plasma versus carboxytherapy in the treatment of periorbital dark circles: A split-face study. J Cosmet Dermatol 21(10):4332–4338. 10.1111/jocd.15051 Ellabban NF, Eyada M, Nada H, Kamel N (2019) Efficacy and tolerability of using platelet-rich plasma versus chemical peeling in periorbital hyperpigmentation. J Cosmet Dermatol 18(6):1680–1685. 10.1111/jocd.12964 Fabi S et al (2023) Effectiveness of Volbella (VYC-15L) for Infraorbital Hollowing: Patient-Reported Outcomes from a Prospective, Multicenter, Single-Blind, Randomized, Controlled Study, Aesthet Surg J , vol. 43, no. 11, pp. 1357–1366, Nov. 10.1093/asj/sjad100 Ghandehari R, Robati RM, Niknezhad N, Hajizadeh N, Tehranchinia Z (2022) Efficacy and safety of fractional CO2 laser and tranexamic acid versus microneedling and tranexamic acid in the treatment of infraorbital hyperpigmentation. J Dermatological Treat 33(3):1391–1396. 10.1080/09546634.2020.1819527 Hamdi H et al (2023) Evaluation of the Effect of Artemisia Absinthium L. Eye-Cream on Infra-Orbital Dark Circle: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. GMJ 12:2413. 10.31661/gmj.v12i0.2413 Iranmanesh B, Rastaghi F, Hashemi NS, Kaveh R (2024) Comparison of the Effectiveness of Platelet-Rich Plasma Versus Tranexamic Acid Plus Vitamin C Mesotherapy in the Treatment of Periorbital Hyperpigmentation: A Split-Site, Randomized Clinical Trial. J Cosmet Dermatol 23(12):4066–4071. 10.1111/jocd.16548 Kadry A, Gamal A, Alkhalifah A, Ibrahim SMA (2023) Efficacy of Platelet-Rich Plasma Versus Autologous Fat Transfer With Nanofat in the Treatment of Infraorbital Dark Circles: A Single-Blinded Randomized Comparative Clinical Trial. Dermatol Surg 49(3):247–252. 10.1097/DSS.0000000000003697 Khan I, Nasr N, Habib A, Jabin I, Iram S, Iram S (2023) Comparison of Carboxy Therapy and Platelet-Rich Plasma Therapy in Patients With Periorbital Hyperpigmentation. J Popul Ther Clin Pharmacol 30(1):2259–2265. 10.53555/jptcp.v30i17.2943 Lu Y et al (2025) Platelet-Rich Plasma Injection Combined With Q-Switched Ruby Laser in the Treatment of Periorbital Hyperpigmentation. J Cosmet Dermatol 24(1):1–6. 10.1111/jocd.16598 Nilforoushzadeh MA et al (2021) Assessing the effectiveness of the combination therapy with fractional Er-YAG laser and platelet-rich plasma in treatment of periorbital dark circles patients: A clinical trial. J Cosmet Dermatol 20(11):3526–3536. 10.1111/jocd.14036 Nilforoushzadeh MA, Heidari-Kharaji M, Alavi S, Zolghadr S, Mahmoudbeyk M, Nikkhah N (2021) Comparison of carboxy therapy and fractional Q-switched ND:YAG laser on periorbital dark circles treatment: a clinical trial. Lasers Med Sci 36(9):1927–1934. 10.1007/s10103-021-03274-5 Nofal E, Elkot R, Nofal A, Eldesoky F, Shehata S, Sami M (2018) Evaluation of carboxytherapy and platelet-rich plasma in treatment of periorbital hyperpigmentation: A comparative clinical trial. J Cosmet Dermatol 17(6):1000–1007. 10.1111/jocd.12478 Ohshima H et al (2009) Effects of vitamin C on dark circles of the lower eyelids: Quantitative evaluation using image analysis and echogram. Skin Res Technol 15(2):214–217. 10.1111/j.1600-0846.2009.00356.x Nann Phoo TS, PHOO MON1, THE EFFICACY OF 2% Andrographis paniculata EXTRACT CREAM IN REDUCING PERIORBITAL WRINKLES AND HYPERPIGMENTATION (2025), vol. 3, no. 3, pp. 3–4 Ranjan R, Sarkar R, Garg V, Gupta T (2016) A comparative study of two modalities, 4% hydroquinone versus 30% salicylic acid in periorbital hyperpigmentation and assessment of quality of life before and after treatment, Indian J Dermatol , vol. 61, no. 4, pp. 413–417, Jul. 10.4103/0019-5154.185707 Roohaninasab M et al (2024) The investigation and comparison of the efficacy and safety of stromal vascular fraction (SVF), platelet rich plasma (PRP), and 1064-nm Q-switched Nd:YAG laser in reducing nanofat treated infraorbital dark circles and wrinkles: A controlled blinded random. Skin Res Technol 30(6):1–12. 10.1111/srt.13793 Roshdy OH, Abd Elall HM, Eid AA (2022) A randomized comparative study of the effect of two different flow rates of carboxytherapy in the treatment of infraorbital dark circles. J Cosmet Dermatol 21(9):4020–4027. 10.1111/jocd.14714 Mohamed Shalash A, Moustafa Fawzy M, Naiem Elfar N, Ramzy Ghaly N (Jan. 2023) Comparison between Efficacy of Carboxytherapy, Plasma Gel Injection and Mesotherapy in Treatment of Periorbital Dark Circles. J Adv Med Med Res 8–17. 10.9734/jammr/2023/v35i24939 Wu X, Liu Y, Zhu J, Yu W, Lin X (2022) A Prospective Trial of the Microneedle Fractional Radiofrequency System Application in the Treatment of Infraorbital Dark Circles. Clin Cosmet Investig Dermatol 15:1293–1300. 10.2147/CCID.S372409 Yu CQ, Xu XG, Chen HD, Li YH (2021) Clinical efficacy and safety of nano-microneedle-assisted phenylethyl resorcinol for the treatment of infraorbital dark circles. J Cosmet Dermatol 20(3):884–889. 10.1111/jocd.13641 Zaheri H, Beyzaee AM, Rokni GR, Patil A, Golpour M, Goldust M (2023) Comparison of the efficacy of carboxytherapy versus fractional CO2 laser therapy for the treatment of periorbital dark circles: A randomized clinical trial. J Cosmet Dermatol 22(2):512–516. 10.1111/jocd.15337 Zamanian A, Azizi M, Ghasemi M, Behrangi E, Naeji S (2019) Comparing the effectiveness of fractional CO 2 laser and the combination therapy with micro-needling and topical 10% trichloroacetic acid to remove infra-orbital dark circles in Tehran women. J Cosmet Laser Therapy 21(2):61–64. 10.1080/14764172.2017.1341047 Pour Mohammad A, Zeinali R, Jafary P, Mortaja M, Jafarzadeh A, Goodarzi A (2025) The First Systematic Review and Meta-Analysis of Pharmacological and Nonpharmacological Procedural Treatments of Dark Eye Circles (Periorbital Hyperpigmentations): One of the Most Common Cosmetic Concerns, Dermatol Ther , vol. no. 1, 2025. 10.1155/dth/9155535 Seirafianpour F et al (2024) Effectiveness, safety, and patient satisfaction of carboxytherapy as an adjunctive treatment for periorbital hyperpigmentation. Skin Res Technol 30(3):1–7. 10.1111/srt.13651 Additional Declarations No competing interests reported. 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08:14:32","extension":"xml","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":159343,"visible":true,"origin":"","legend":"","description":"","filename":"956b65e5bc3d469fb9ed1a4fd7bb06e81structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7537721/v1/becc51ac1270e0612046557a.xml"},{"id":96366803,"identity":"79f31edc-64de-443b-b1d3-d9080c48fb70","added_by":"auto","created_at":"2025-11-20 10:11:55","extension":"html","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":177996,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7537721/v1/ccda6135e6c28a463b0e3d31.html"},{"id":96354982,"identity":"e535faa6-da72-48d7-9704-04739dd873ce","added_by":"auto","created_at":"2025-11-20 08:14:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":255058,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrisma flow chart\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePRISMA flowchart, a summary of the process of selecting studies included in this review.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7537721/v1/2673d7cb98b34d475f973d8e.png"},{"id":96354976,"identity":"b0cfdf91-87f6-429d-9c66-af168da96d62","added_by":"auto","created_at":"2025-11-20 08:14:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3652968,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flowchart, a summary of the process of selecting studies included in this review.\u003c/p\u003e\n\u003cp\u003eForest plots Single Arm Meta-analysis. A) Improvement \u0026gt;50%, B) Improvement \u0026gt;75%, C)VAS score, D)Melanin Index, E) Erythema Index, F) Patient satisfaction: Good, G) Patient satisfaction: excellent.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7537721/v1/4aa22158cf744da3d2f4eba9.png"},{"id":96367067,"identity":"be696d24-6b1c-4cee-9101-1dccb6c7e629","added_by":"auto","created_at":"2025-11-20 10:12:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":407232,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel Plots Meta-analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunnel plots Single Arm Meta-analysis. A) Improvement \u0026gt;50% B) Improvement \u0026gt;75% C) VAS score D) Melanin Index E) Erythema Index F) Patient satisfaction: Good G) Patient satisfaction: excellent\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7537721/v1/0cdbfb386cbf2ff83a9b2d9d.png"},{"id":96369453,"identity":"b0f84b22-a0b1-4d89-b678-b7679b244023","added_by":"auto","created_at":"2025-11-20 10:20:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5552627,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7537721/v1/1897d9bb-1f87-4317-943f-61ee6523406f.pdf"},{"id":96354981,"identity":"4f80f2c0-516f-4d7f-9cf2-d8afd52c073d","added_by":"auto","created_at":"2025-11-20 08:14:31","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":7106966,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryPeriorbitalhyperpigmentation.docx","url":"https://assets-eu.researchsquare.com/files/rs-7537721/v1/7da750b02f39e2e47138b0f7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Treatments in Periorbital Hyperpigmentation: A Systematic Review and Single-Arm Meta- Analysis of Clinical Trials","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePeriorbital hyperpigmentation (POH) is a common dermatological condition, characterized by bilateral darkening around the eyes, sometimes spreading to adjacent facial areas. Although considered a cosmetic concern, POH can negatively affect emotional well-being and quality of life (QOL)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite its frequency, data remains limited. An Indian study reported a 30.8% prevalence, predominantly among individuals aged 16 to 25 years[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePOH is classified into pigmented, vascular, and structural which is associated with post-inflammatory hyperpigmentation (PIH)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Accurate subtype determination is essential for guiding personalized treatment strategies. Multiple therapeutic options can be employed for POH, with topical agents commonly used as first-line therapy. Hydroquinone, a widely used depigmenting agent and kojic acid interfering with melanogenesis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. For refractory or severe POH, laser therapy offers a viable treatment option [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Structural POH can be addressed with fillers, common filler material options include hyaluronic acid, calcium hydroxyapatite, and autologous fat grafts; the latter is especially beneficial for lower eyelid skin and increased vascular visibility or prominent orbicularis oculi muscle[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, they are not a replacement for surgical correction in cases of significant orbital fat prolapse. In such cases, blepharoplasty remains an effective surgical intervention for hyperpigmentation caused by fat deposits or excess skin[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although some treatments demonstrate benefits in particular cases, no consensus exists on the optimal approach to managing overall POH, reinforcing the importance of additional comparative research. Although POH is a common dermatologic condition with cosmetic and psychosocial implications, the management remains limited, and no standardized treatment guidelines exist. This study provides a comprehensive and up-to-date synthesis of current therapies using meta-analytic methods to assess and compare their effectiveness. By identifying the most effective strategies, we aim to support evidence-based clinical decision-making and address the psychosocial and emotional burden associated with POH.\u003c/p\u003e"},{"header":"2. Methodology","content":"\u003cp\u003eThe present systematic review followed the recommendations and criteria established by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. We pre-registered the protocol at the International Prospective Register of Systematic Review (PROSPERO) with the identifier code CRD420251082683[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] .\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Eligibility criteria: Type of study, participants, and intervention\u003c/h2\u003e\u003cp\u003e We conducted a systematic review and meta-analysis of relevant studies published from the inception of the database to the present, including only randomized clinical trials (RCTs) and cross over studies, in English and Spanish. Studies were excluded if they were duplicates or if the necessary data could not be obtained, or a response from the original author could not be received. This study included participants of all ages undergoing any type of treatment for periorbital hyperpigmentation. Eligible interventions may include, but are not limited to, platelet-rich plasma (PRP), chemical peels, topical depigmenting agents (e.g., hydroquinone, kojic acid), lasers, fillers, autologous fat grafting, baric oxygen, among others. Only studies that evaluated any of these interventions, compared directly with standard care, placebo, or other interventions, were included.\u003c/p\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003e2.1.1. Outcomes\u003c/h2\u003e\u003cp\u003ePrimary outcomes will include clinical improvement in periorbital hyperpigmentation, measured by blinded photographic assessments, pigmentation grading scales, colorimetric analysis, and patient-reported satisfaction (e.g., VAS or global ratings). Studies reporting response categories (e.g., excellent, good, none) or changes in skin thickness and density will also be included.\u003c/p\u003e\u003cp\u003eSecondary outcomes will include adverse events (e.g., pain, bruising, edema, itching, erythema), and changes in quality of life (e.g., DLQI). Studies must report at least one predefined outcome to be eligible.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\u003ch2\u003e2.1.2. Searching methods\u003c/h2\u003e\u003cp\u003eWe initially conducted a systematic search on June 26th, 2025, on PubMed/MEDLINE, Cochrane, Scopus, Web of Science, EMBASE, CINAHL and Google Scholar using the following terms: of \u0026ldquo;periorbital hyperpigmentation\u0026rdquo;, \u0026ldquo;dark circles\u0026rdquo;, \u0026ldquo;infraorbital pigmentation\u0026rdquo;, and various therapeutic interventions such as \u0026ldquo;lasers\u0026rdquo;, \u0026ldquo;chemical peels\u0026rdquo;, \u0026ldquo;fillers\u0026rdquo;, \u0026ldquo;platelet-rich plasma\u0026rdquo;, \u0026ldquo;topical depigmenting agents\u0026rdquo;, among others. We have provided all detailed search strategies in the supplementary material (Supplementary Tables\u0026nbsp;1\u0026ndash;7).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e2.1.3. Selection of studies\u003c/h2\u003e\u003cp\u003eWe exported all references to Rayyan (Rayyan Systems Inc., Cambridge, MA, USA) and removed duplicates[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].Two authors independently (A.C.L. and M.V.S.) completed the eligibility assessment, first by title and abstract analysis and, subsequently, by full-text assessment. In disagreements between reviewers, a third reviewer (Y.C.C.) helped reach a consensus.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.1.4. Data extraction\u003c/h2\u003e\u003cp\u003e Two independent reviewers extracted the data (E.M.C. and Y.C.C.), resolving disagreements through consensus.. In cases of multiple overlapping reports from the same study, we included the report with the most relevant information or the earliest publication date. Extracted data included sample sizes, intervention types, and measured outcomes. We employed conventional data extraction methods, complemented by specialized tools such as WebPlotDigitizer (Automeris, Austin, TX, USA) for digitizing data from graphs, Cochrane Calculator for statistical conversions, and StatsToDo for advanced calculations[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These outcomes comprised clinical improvement in periorbital hyperpigmentation, measured by blinded photographic assessments, pigmentation grading scales, colorimetric analysis, patient-reported satisfaction (e.g., VAS or global ratings) and response categories (e.g., excellent, good, none) or changes in skin thickness. Additional extracted data included subgroup characteristics, such as country of study, risk of bias levels, and study design.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\u003ch2\u003e2.1.5. Assessment of risk of bias in included studies\u003c/h2\u003e\u003cp\u003eTo assess the quality of the studies included in the systematic review, according to the Cochrane guidelines we applied the Cochrane RoB 2.0 tool for randomized controlled trials (RCTs)[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] and the ROBINS-I V2 tool for non-randomized controlled trials[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Two independent reviewers (A.C.L and M.V.S) evaluated the risk of bias in each study, considering the specific criteria and guidelines provided by the respective tools. We resolved discrepancies between reviewers through discussion with a third, blinded reviewer (S.A.B.).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003e2.1.6. Statistical analysis\u003c/h2\u003e\u003cp\u003eA meta-analysis was performed using R version 3.4.3[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The pooled effect of the outcomes was examined using a random-effects meta-analysis (DerSimonian-Laird approach)[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Whenever the number of studies reporting an outcome of interest was insufficient, only a qualitative analysis of the results was performed. Effect sizes were expressed as Relative Risk (RR), Mean difference (MD), proportions or standardized mean difference (SMD) and 95% CI. The I\u0026sup2; statistic assessed heterogeneity, and the following cut-off values used for interpretation: \u0026lt;25, 25\u0026ndash;50, and \u0026gt;\u0026thinsp;50% were considered small, medium, and large heterogeneity respectively[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. We initially planned to conduct a network meta-analysis (NMA) to compare the relative effectiveness of the included interventions. However, during data extraction, we found that the network was disconnected, with many interventions lacking a shared comparator. This prevented construction of a coherent network. Consequently, we performed single-arm meta-analyses for each intervention separately, without direct or indirect comparisons between treatments. As originally planned, sensitivity analyses according to the leave-one-out method were performed to determine the influence of individual studies on the overall effect, using diagnostic plots proposed by Viechtbauer and Cheung[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Egger's regression test examined publication bias when ten or more reports with the same outcome were available[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Study selection\u003c/h2\u003e\u003cp\u003eOriginally, we identified 1384 potential articles across seven databases. After removing 802 duplicate articles, we conducted a screening based on title and abstract, leading to the exclusion of 500 articles. We sought 82 articles for full-text retrieval and eligibility assessment, of which 52 were excluded. A total of 31 studies were included in this review. Additionally, 1 study identified through previous reviews were included, resulting in a total of 31 studies in this review. We summarized this process in our PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Characteristics of included studies\u003c/h2\u003e\u003cp\u003eWe analyzed 31 RCTs compromising 1,257 patients across eight countries. Most studies originated from Iran (35%) and Egypt (29%), followed by China (10%), India (10%) and the United States (7%); smaller contributions came from Japan, Pakistan and Thailand (3% each). Melanin Index was assessed in 8 of the 31 studies, 16.13% reported statistically significant improvements with carboxytherapy, placebo, andographins, artemisinin, laser monotherapy, laser combined with placebo and PRP combined with laser; 9.68% showed no effect and 74.19% of studies did not report this outcome. Erythema Index was evaluated in 5 studies with statistically significant improvement observed in 6.45% of studies with artemisinin, carboxytherapy and placebo. Conversely 9.68% showed no statistical difference and 83.87% didn\u0026rsquo;t report this outcome. Improvement of \u0026ge;\u0026thinsp;50% by physician assessment was reported in 15 studies where 12.90% demonstrated significant improvement with carboxytherapy, placebo, PRP, TCA combined with lactic acid peeling and plasma gel injection; 35.48% found no significant results and 51.61% of studies did not report this outcome. \u0026ge;75% improvement was assessed in 18 studies. From which 16% showed a significant trend favoring carboxytherapy, CO2 laser, placebo, PRP, TCA plus Lactic acid peeling and plasma gel injection, 42% of studies found no significant difference and 42% did not include this outcome. VAS outcomes were reported in 6 studies. Of these 16.12% reported significant benefit from interventions including carboxytherapy, laser (alone or with placebo), PRP alone and combined with laser and plasma gel injections. One study (3.22%) found no significant difference and 80.65% of studies did not include this outcome. A good and excellent patient satisfaction was evaluated in 16 studies, from which 29% reported statistically significant patient satisfaction with PRP alone, carboxytherapy, PRP combined with laser, laser combined with placebo, fat injection alone and with combination therapy, TCA combined with lactic acid peel, Andrographis, placebo, microneedling combined with TCA and CO2 laser; 22.58% found no effet and 48.38% of articles did not report these outcomes. PRP and carboxytherapy were the most frequently reported and consistently demonstrated improvement across multiple outcomes, highlighting their role as therapeutic options. We summarized this information in (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)22\u0026ndash;52.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGeneral outcome of included studies\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAuthor and Year\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTypes of Interventions\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSample size per intervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFollow up (weeks)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKey points\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAfzal N, et al., 2024\u003c/b\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTHDA\u0026thinsp;+\u0026thinsp;AZ and\u003c/p\u003e\u003cp\u003eTHDA alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTHDA and AZ significantly improved pigmentation, and redness, while THDA alone worsened wrinkles and erythema.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAhmadraji F, et al., 2015\u003c/b\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT-Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEmu oil\u0026thinsp;+\u0026thinsp;Vitamin k\u0026thinsp;+\u0026thinsp;Caffeine Pad\u003c/p\u003e\u003cp\u003eAnd\u003c/p\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eThe Emu oil\u0026thinsp;+\u0026thinsp;vitamin K\u0026thinsp;+\u0026thinsp;caffeine treatment improved elasticity and decreased in dark circles. In contrast, the placebo showed no elasticity improvement, and worsened pigmentation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAhmed N, et al., 2019\u003c/b\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEgypt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarboxytherapy,\u003c/p\u003e\u003cp\u003eTCA\u0026thinsp;+\u0026thinsp;LA Peeling\u003c/p\u003e\u003cp\u003eAnd Vitamin C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCarboxytherapy, chemical peeling, and vitamin C mesotherapy all effectively reduced periorbital pigmentation, though mesotherapy was less tolerable.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAsilian A, et al., 2021\u003c/b\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT-Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarboxytherapy and PRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eThe study concluded that both PRP and carboxytherapy resulted in insignificant changes.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAssaf, et al., 2022\u003c/b\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEgypt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT - Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCarboxytherapy and\u003c/p\u003e\u003cp\u003eMicroneedling with topical Glutathione\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCarboxytherapy showed significantly greater VAS improvement and higher patient satisfaction than microneedling with glutathione during both treatment and follow-up.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBehrangi E, et al., 2022\u003c/b\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFractional CO2 laser therapy and Fractional CO2 laser\u0026thinsp;+\u0026thinsp;PRP treatments\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAdding PRP to CO₂ laser reduced periorbital hyperpigmentation by 25% with erythema resolving faster.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBudania A, et al., 2020\u003c/b\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT - Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNovel PRP and Conventional PRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBoth novel and conventional PRP significantly improved DLQI and reduced VAS scores from baseline.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDayal S, et al., 2019\u003c/b\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20% glycolic acid peeling,\u003c/p\u003e\u003cp\u003e15% lactic acid peeling and\u003c/p\u003e\u003cp\u003e12% ferulic acid peeling\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAll three peels significantly reduced under-eye hyperpigmentation, with glycolic acid showing the greatest improvement over lactic and ferulic acid.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDiab H., et al., 2021\u003c/b\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEgypt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSplit face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRP and Plasma gel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePRP and plasma gel were both effective for periorbital rejuvenation, with plasma gel showing better improvement. However, neither significantly reduced melanin concentration. Both treatments were well tolerated.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEl-Tahlawi S, et al., 2022\u003c/b\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEgypt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSplit face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRP injections\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003eCarboxytherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eThe study concluded that PRP was more effective and tolerable than carboxytherapy for treating periorbital dark circles; both treatments had high patient and doctor satisfaction, with no significant difference in pain during the procedure.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEllabban, et al., 2019\u003c/b\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEgypt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePeeling agent: TCA 3.75% + LA 15%\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003eAutologous PRP injections\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eChemical peeling showed significantly better results than PRP, reporting good improvement and most were very pleased to be extremely satisfied.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFabi S, et al., 2023\u003c/b\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eVYC-15L\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e135\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAt 3- and 12-month post-treatment, most VYC-15L patients were satisfied, not bothered by dark circles, and would recommend the treatment.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGhandehari, et al., 2020\u003c/b\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eClinical trial - Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTranexamic acid\u0026thinsp;+\u0026thinsp;CO2 Laser\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003eTranexamic acid\u0026thinsp;+\u0026thinsp;Microneedling\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eThe laser-treated side showed significantly greater improvement in infraorbital hyperpigmentation by day 60. By day 150, both sides showed similar improvement.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHamdi H, et al., 2022\u003c/b\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eArtemisia extract eye cream\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003eplacebo eye cream\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eThe Artemisia absinthium eye cream group showed greater improvements than placebo, with larger reductions in color difference, erythema and melanin, as well as a greater increase in lightness.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIranmanesh, et al., 2024\u003c/b\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT - Split Site\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntradermal injection of PRP\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003eIntradermal injection of tranexamic acid\u0026thinsp;+\u0026thinsp;Vitamin C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePRP favored for showing higher satisfaction score.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKadry A, et al., 2023\u003c/b\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEgypt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRP and\u003c/p\u003e\u003cp\u003eAutologous Fat\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAutologous fat treatment was significantly more effective than PRP in improving periorbital hyperpigmentation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKhan I, et al., 2023\u003c/b\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePakistan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRP and carboxytherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePRP had more excellent responders but higher pain scores than carboxytherapy.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLu Y, et al., 2024\u003c/b\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRP injection after Q-switched ruby laser treatment and\u003c/p\u003e\u003cp\u003eQ-switched ruby laser only\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eThe combined PRP\u0026thinsp;+\u0026thinsp;Q-switched ruby laser treatment showed greater and longer-lasting improvements in hyperpigmentation, and patient satisfaction compared to laser alone.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNilforoushzadeh M, et al., 2020\u003c/b\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSplit face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFractional Er: YAG laser treatment\u0026thinsp;+\u0026thinsp;PRP\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003eFractional Er: YAG laser treatment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFractional Er:YAG laser with PRP significantly reduced melanin index and VAS scores, while the laser alone only improved VAS scores.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNilforoushzadeh M, et al., 2021\u003c/b\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ecarboxytherapy\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003eQ-switched Nd:YAG laser.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBoth treatments significantly reduced melanin index and improved VAS scores, but carboxytherapy showed greater VAS improvement than Q-switched Nd:YAG laser.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNofal E. et al., 2018\u003c/b\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEgypt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT-Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRP and carboxytherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePRP and carboxytherapy have similar efficacy for periorbital hyperpigmentation, but PRP causes more severe, persistent side effects, while carboxytherapy has milder, transient ones and is better tolerated.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOhshima H, et al., 2009\u003c/b\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eJapan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eClinical trial - Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eANa, Placebo, and\u003c/p\u003e\u003cp\u003eAG\u0026thinsp;+\u0026thinsp;placebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eANa significantly reduced EI compared to vehicles, while vitamin C and AG showed no significant difference in EI change. MI changes were not significantly different for vitamin C.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePhoo Mon N, et al., 2025\u003c/b\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThailand\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT-Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAndrographis paniculata extract cream\u003c/p\u003e\u003cp\u003eAnd\u003c/p\u003e\u003cp\u003ePlacebo cream\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAndrographis paniculata cream significantly improves skin elasticity, and reduces hyperpigmentation without harmful side effects, while placebo showed no significant improvement.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRanjan R, et al., 2016\u003c/b\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4% hydroquinone\u003c/p\u003e\u003cp\u003eAnd\u003c/p\u003e\u003cp\u003e30% salicylic acid peel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBoth hydroquinone and salicylic acid significantly improved VAS scores and reduced DLQI.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRoohaninasab M, et al., 2024\u003c/b\u003e[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNanofat\u0026thinsp;+\u0026thinsp;SVF\u003c/p\u003e\u003cp\u003eNanofat\u0026thinsp;+\u0026thinsp;PRP\u003c/p\u003e\u003cp\u003eNanofat\u0026thinsp;+\u0026thinsp;Nd:YAG laser\u003c/p\u003e\u003cp\u003eNanofat only\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCombined nanofat injections with SVF, PRP, or 1064-nm Q-switched Nd:YAG laser significantly outperformed nanofat alone in reducing under-eye darkness. Specifically, nanofat\u0026thinsp;+\u0026thinsp;PRP improved complete and dermal density, while nanofat\u0026thinsp;+\u0026thinsp;laser enhanced color and dermal thickness.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRoshdy O, et al., 2021\u003c/b\u003e[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEgypt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ecarboxytherapy 30 ml/mn and carboxytherapy 60 ml/mn\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBoth standard and high dose carboxytherapy significantly reduced melanin and erythema indices.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eShalash A, et al., 2023\u003c/b\u003e[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEgypt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBilateral injection of PRP gel,\u003c/p\u003e\u003cp\u003eBilateral intradermal injection of CO2 with carboxytherapy machine\u003c/p\u003e\u003cp\u003eAnd\u003c/p\u003e\u003cp\u003eIntradermal injection of vitamin C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePRP and vitamin C significantly improved PODC grading, while carboxytherapy did not; however, no significant differences were found between the three groups.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWu X, et al.\u003c/b\u003e,\u003c/p\u003e\u003cp\u003e\u003cb\u003e2022\u003c/b\u003e[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eProspective - Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMicroneedle Fractional Radiofrequency\u003c/p\u003e\u003cp\u003eAnd no treatment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMicroneedling improved periorbital hyperpigmentation without reducing melanin index, while placebo showed no significant effects.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eYu C, et al., 2020\u003c/b\u003e[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT- Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePhenylethyl resorcinol gel\u0026thinsp;+\u0026thinsp;nano-microneedle,\u003c/p\u003e\u003cp\u003ePhenylethyl resorcinol gel,\u003c/p\u003e\u003cp\u003ePlacebo gel\u0026thinsp;+\u0026thinsp;nano-microneedle\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003ePlacebo gel\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePhenylethyl resorcinol gel, especially when combined with nano-microneedling, significantly reduced melanin index, whereas placebo and microneedling alone did not.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eZaheri, et al., 2022\u003c/b\u003e[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT - Split face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSub-cutaneous or intradermal injection of pure carbon dioxide as carboxytherapy\u003c/p\u003e\u003cp\u003eand\u003c/p\u003e\u003cp\u003eFractional CO2 laser therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFractional CO2 laser therapy is a better treatment with fewer side effects than carboxytherapy, but larger studies are needed to confirm this.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eZamanian A, et al., 2017\u003c/b\u003e[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMicroneedling\u0026thinsp;+\u0026thinsp;TCA and CO2 Laser\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCO2 Laser showed higher levels of satisfaction on fifth visit and higher response to treatment. However, only in with this intervention was notice side effects such as erythema and irritation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cb\u003eAG\u003c/b\u003e: Ascorbic Acid Glucoside, \u003cb\u003eANa\u003c/b\u003e: Sodium Ascorbate, \u003cb\u003eDLQI\u003c/b\u003e: Dermatology Life Quality Index, \u003cb\u003eLA\u003c/b\u003e: Lactic Acid, \u003cb\u003ePODC\u003c/b\u003e: presumably post-operative pain and dysfunction, \u003cb\u003eSVF\u003c/b\u003e: Stromal Vascular Fraction, \u003cb\u003eTCA\u003c/b\u003e: Trichloroacetic acid, \u003cb\u003eYAG Laser\u003c/b\u003e: Yttrium Aluminum Garnet Laser and \u003cb\u003eVAS\u003c/b\u003e: Visual Analog Scale.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Risk of bias.\u003c/h2\u003e\u003cp\u003eWe evaluated the risk of bias in 27 RCTs using RoB 2.0 tool[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Of these, 6 studies (22%) were deemed high risk of bias, 7 (26%) had some concerns, and 14 (52%) were deemed low risk (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e). 4 non-randomized studies were assessed with ROBINS-I V2 tool[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], 1 study (25%) showed a moderate risk of bias and 3 studies (75%) were considered low risk (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Overall, 55% of studies were high quality, 26% moderate quality, and 19% low quality.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Meta analysis\u003c/h2\u003e\u003cp\u003eThe planned network meta-analysis was not feasible because the identified studies did not form a connected network, with multiple isolated intervention nodes and no shared comparators. Consequently, single-arm meta-analyses were performed instead.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003e3.4.1\u0026thinsp;\u0026gt;\u0026thinsp;50% improvement\u003c/h2\u003e\u003cp\u003eIn this meta-analysis, data were synthesized from 30 studies encompassing a total of 718 participants. The pooled proportion of successful outcomes across all interventions was 0.51 (95% CI: 0.38 to 0.65; I\u0026sup2; = 77.4%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The prediction interval ranged from 0.09 to 0.92. The funnel plot revealed asymmetry suggestive of potential publication bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Egger\u0026rsquo;s test was not performed due to the inclusion of fewer than ten studies per subgroup. Subgroup analysis by intervention type demonstrated significant differences among treatment modalities (χ\u0026sup2;₁₇ = 87.10, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Carboxytherapy alone yielded a pooled proportion of 0.50 (95% CI: 0.27 to 0.73; I\u0026sup2; = 74.8%), indicating moderate heterogeneity across included studies. In contrast, CO₂ laser demonstrated a pooled proportion of 0.68 (95% CI: 0.45 to 0.85) with no observed heterogeneity (I\u0026sup2; = 0%). Both interventions contributed to the overall model and were associated with favorable response rates.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\u003ch2\u003e3.4.2\u0026thinsp;\u0026gt;\u0026thinsp;75% improvement\u003c/h2\u003e\u003cp\u003eIn this meta-analysis, data were synthesized from 31 studies comprising a total of 646 participants. The pooled proportion of successful outcomes across all interventions was 0.24 (95% CI: 0.18 to 0.31; I\u0026sup2; = 53.4%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The prediction interval ranged from 0.08 to 0.52. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Egger\u0026rsquo;s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis by intervention type revealed statistically significant differences (χ\u0026sup2;₁₁ = 27.48, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Among the interventions with multiple observations, platelet-rich plasma (PRP) demonstrated a pooled proportion of 0.27 (95% CI: 0.11 to 0.52; I\u0026sup2; = 71.0%), indicating high variability across studies. In contrast, carboxytherapy showed a more consistent pooled effect of 0.26 (95% CI: 0.17 to 0.37; I\u0026sup2; = 15.3%), suggesting homogeneity among included studies. Both interventions contributed substantially to the overall model and showed clinically meaningful effects, with PRP showing wider confidence intervals due to greater heterogeneity.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section3\"\u003e\u003ch2\u003e3.4.3 Visual Analogue scale\u003c/h2\u003e\u003cp\u003eIn this meta-analysis, we included 12 studies with a combined total of 266 participants. The pooled mean VAS score across all interventions was 4.89 (95% CI: 4.22 to 5.57; I\u0026sup2; = 95.7%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). The prediction interval ranged from 2.23 to 7.56. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Egger\u0026rsquo;s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis revealed significant differences in treatment efficacy (χ\u0026sup2;\u003csub\u003e7\u003c/sub\u003e = 172.28, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). PRP demonstrated a pooled VAS of 4.77 (95% CI: 3.12 to 6.43; I\u0026sup2; = 95.8%), while carboxytherapy yielded a pooled score of 4.69 (95% CI: 3.97 to 5.40; I\u0026sup2; = 67.4%). Both interventions showed clinically significant improvements, although substantial heterogeneity was observed, particularly within the PRP subgroup.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section3\"\u003e\u003ch2\u003e3.4.4 Melanin Index\u003c/h2\u003e\u003cp\u003eIn this meta-analysis, we included 17 studies with a combined total of 285 participants. The pooled mean melanin index across all interventions was 165.73 (95% CI: 141.76 to 189.69; I\u0026sup2; = 97.7%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). The prediction interval ranged from 62.47 to 268.99. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). Egger\u0026rsquo;s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis revealed significant differences in melanin index outcomes among treatment modalities (χ\u0026sup2;\u003csub\u003e13\u003c/sub\u003e= 251.41, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Placebo-treated groups exhibited the highest pooled melanin index at 207.91 (95% CI: 104.81 to 311.02; I\u0026sup2; = 98.1%), while carboxytherapy showed a substantially lower pooled index of 75.23 (95% CI: 23.41 to 127.04; I\u0026sup2; = 97.7%). Both subgroups contributed significantly to the overall model. Notably, heterogeneity was high in both groups.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section3\"\u003e\u003ch2\u003e3.4.5 Erythema Index\u003c/h2\u003e\u003cp\u003eIn this meta-analysis, we included 11 studies with a combined total of 207 participants. The pooled mean erythema index across all interventions was 333.20 (95% CI: 240.64 to 425.76; I\u0026sup2; = 99.5%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). The prediction interval ranged from \u0026minus;\u0026thinsp;29.09 to 695.49. The funnel plot demonstrated asymmetry suggestive of potential publication bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eE). Egger\u0026rsquo;s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis revealed significant differences in erythema scores among treatment modalities (χ\u0026sup2;₁₀ = 2014.17, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Platelet-rich plasma combined with laser demonstrated the highest pooled erythema index at 394.40 (95% CI: 380.92 to 407.88), while carboxytherapy high dose showed the lowest pooled value at 41.09 (95% CI: 28.58 to 53.60). Both subgroups contributed substantially to the overall model, high level of heterogeneity was observed.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section3\"\u003e\u003ch2\u003e3.4.6 Patient Satisfaction: Good or \u0026gt;\u0026thinsp;50%\u003c/h2\u003e\u003cp\u003eThis meta-analysis included 36 studies with 814 participants. The pooled proportion of successful outcomes across all interventions was 0.59 (95% CI: 0.51 to 0.67; I\u0026sup2; = 64.5%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eF), with a prediction interval of 0.25 to 0.86. Funnel plot asymmetry suggested potential publication bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eF). Egger\u0026rsquo;s test was not conducted due to the small number of studies within individual subgroups. Subgroup analysis by intervention type revealed statistically significant differences (χ\u0026sup2;\u003csub\u003e22\u003c/sub\u003e = 65.75, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Carboxytherapy demonstrated a pooled efficacy of 0.52 (95% CI: 0.38 to 0.66; I\u0026sup2; = 32.8%). PRP yielded a pooled proportion of 0.43 (95% CI: 0.24 to 0.64; I\u0026sup2; = 63.1%), reflecting moderate heterogeneity. Vitamin C achieved a pooled effect of 0.64 (95% CI: 0.11 to 0.96; I\u0026sup2; = 0.00%) with no heterogeneity, TCA combined with lactic acid peeling showed a pooled proportion of 0.72 (95% CI: 0.00 to 1.00; I\u0026sup2; = 76.1%), with substantial heterogeneity and imprecise confidence intervals.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section3\"\u003e\u003ch2\u003e3.4.7 Patient Satisfaction: Excellent or \u0026gt;\u0026thinsp;75%\u003c/h2\u003e\u003cp\u003eThis meta-analysis included 31 studies with 684 participants. The pooled success rate was 0.24 (95% CI: 0.17 to 0.32; I\u0026sup2; = 64.6%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eG), with a prediction interval od 0.05 to 0.63. Funnel plot asymmetry suggested potential publication bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eG). Egger\u0026rsquo;s test was not performed due to few studies per subgroup. Subgroup analysis by intervention type revealed statistically significant differences (χ\u0026sup2;\u003csub\u003e21\u003c/sub\u003e = 64.6, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Carboxytherapy demonstrated a pooled efficacy of 0.21 (95% CI: 0.07 to 0.47; I\u0026sup2; = 56.4%), indicating moderate heterogeneity. PRP yielded a pooled proportion of 0.18 (95% CI: 0.11 to 0.28; I\u0026sup2; =0.00) and TCA combined with lactic acid peeling showed a pooled proportion of 0.20 (95% CI: 0.00 to 1.00; I\u0026sup2; = 72.5%), though the wide confidence interval and high heterogeneity suggest greater uncertainty in the estimated effect.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis systematic review and meta-analysis evaluate POH treatments using clinical improvement thresholds. Carboxytherapy showed a pooled proportion of 0.50 (95% CI: 0.27 to 0.73; I\u0026sup2; = 74.8%), indicating that half of the treated patient achieved\u0026thinsp;\u0026gt;\u0026thinsp;50% clinical improvement. CO₂ yielded a pooled proportion of 0.68 (95% CI: 0.45 to 0.85), suggesting greater efficacy with consistent results and no observed heterogeneity (I\u0026sup2; = 0%). Similarly, trends toward \u0026gt;\u0026thinsp;75% improvement were observed with carboxytherapy 0.26 (95% CI: 0.17 to 0.37; I\u0026sup2; = 15.3%) and PRP (0.27; 95% CI: 0.11 to 0.52; I\u0026sup2; = 71.0%). These findings align with a prior meta-analysis conducted by Mohammad A. et al, who reported good (50\u0026ndash;75%) responses with PRP and carboxytherapy, and excellent (\u0026gt;\u0026thinsp;75%) improvement with chemical peel and PRP, though the latter was based on a single study. VAS outcomes, improved with carboxytherapy, laser, PRP both alone and combined with laser. Subgroup analysis showed similar VAS score reductions for PRP (pooled VAS reduction of 4.77) and carboxytherapy (4.69) suggesting a decrease in pain after either treatment. The comparable magnitudes may reflect distinct but similarly effective mechanisms given that PRP promotes collagen synthesis, angiogenesis, and epidermal regeneration, whereas carboxytherapy induces transient hypoxia triggering vasodilation and neovascularization [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Heterogeneity, particularly for PRP likely reflects variability in preparation methods, treatment protocols, patient population and subjectivity of VAS scoring, limiting comparability.\u003c/p\u003e\u003cp\u003eIn our qualitative synthesis both carboxytherapy and laser reduced melanin index. Subgroup analysis confirmed this with placebo showing the highest pooled melanin index and carboxytherapy the lowest. However high heterogeneity suggests variability in treatment effects. Regarding erythema index, significant reduction was seen with high dose carboxytherapy achieving the lowest value pooled proportion when compared to PRP, which achieved the highest pooled proportion. The substantial heterogeneity observed may reflect differences in treatment depth, inflammatory response and procedural variables. Although Mohammad A. et al, attempted to assess erythema in a previous meta-analysis, inconsistent reporting across the included studies limited the strength of their conclusions [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]​. Patient satisfaction was evaluated; for \u0026ldquo;good\u0026rdquo; satisfaction (\u0026gt;\u0026thinsp;50% improvement), carboxytherapy (pooled efficacy of 0.52; low heterogeneity), PRP (pooled proportion of 0.43; moderate heterogeneity), vitamin C (pooled effect of 0.64; no heterogeneity) and TCA\u0026thinsp;+\u0026thinsp;lactic acid peeling (pooled proportion of 0.72; high heterogeneity). These results emphasize the subjective improvement by patients, particularly with carboxytherapy. Compared to analysis by Mohammad A., where laser therapies ranked the highest in-patient satisfaction[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. For excellent satisfaction (\u0026gt;\u0026thinsp;75% improvement), carboxytherapy yield a pooled efficacy of 0.21 with moderate heterogeneity, followed by PRP (pooled proportion of 0.18) with no heterogeneity and TCA\u0026thinsp;+\u0026thinsp;lactic acid (pooled proportion of 0.20) which exhibited a wide confidence interval and high heterogeneity. A similar pattern was reported by Mohammad A. et al, where combination therapies, particularly laser, yielded the highest satisfaction, followed by peels, PRP, laser alone, and carboxytherapy[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Despite some discrepancies, our findings consistently support PRP, carboxytherapy, and chemical peels as effective options, reinforcing their relevance in clinical practice.\u003c/p\u003e\u003cp\u003e Currently, no standard guidelines exist for POH management. Topical agents remain most common due to availability and ease of use. For stronger effects, chemical peels are employed, though outcomes vary by skin type. Laser therapies show clinical benefit and patient satisfaction, but efficacy and safety depend on patient selection and device parameters​[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Newer non-invasive options such as PRP and carboxytherapy demonstrate promising efficacy, particularly in vascular subtypes. For structural causes, invasive approaches like fillers or blepharoplasty may be more effective. Dermoscopic subtype identification is essential for individualized care. Beyond aesthetics, POH impacts emotional well-being, underscoring the need for patient-centered treatment.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStrength and limitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003e This review synthesizes evidence from 31 studies, including 11 not assessed in prior reviews, and is among the first to quantitatively evaluate outcomes such as melanin and erythema index. It provides new insights into treatment efficacy and adverse effects of POH therapies. However, a network meta-analysis was not feasible, as initially intended, due to insufficient direct and indirect comparisons. Heterogeneity in study design and the absence of a standardized classification for POH subtypes further limit comparability. Treatments target different etiologies (vascular, pigmentary, structural), underscoring the need for a consistent subtype classification to enable subtype-specific outcomes and head-to-head trials. Our definition of \u0026ldquo;excellent\u0026rdquo; response was revised from \u0026ge;\u0026thinsp;90% to \u0026ge;\u0026thinsp;75% improvement to align with most studies and maintain analytical consistency. Despite these limitations, this review strengthens the evidence base for novel non-invasive therapies, though rigorous trials with standardized subtype definitions and longer follow-up are still needed.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eOur meta-analysis synthesizes evidence on clinical improvement. Findings suggest carboxytherapy and PRP, alone or combined, offer favorable efficacy and safety. Despite heterogeneity, results support non-invasive therapies in POH management. Future studies should use standardized subtype classifications and monitor adverse events to strengthen evidence. This review highlights the importance of individualized, patient-centered approaches and the potential of safe treatments to address both the cosmetic and psychological burden of POH.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePOH — Periorbital hyperpigmentation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePIH — Post-inflammatory hyperpigmentation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eQOL — Quality of life\u003c/p\u003e\n\u003cp\u003ePRP — Platelet-rich plasma\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVAS — Visual analog scale\u003c/p\u003e"},{"header":"Statements and declarations","content":"\u003cp\u003eI. \u0026nbsp; \u0026nbsp; \u0026nbsp;Funding: This research was not funded by any special agency.\u003c/p\u003e\n\u003cp\u003eII. \u0026nbsp; \u0026nbsp;Conflict of interest: All authors declare no conflict of interest. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIII. \u0026nbsp; Availability of data and materials: All the data used to perform this analysis is publicly available in the referenced articles. The rest of the material is at the author\u0026apos;s disposition upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e All data used in this analysis are publicly available in the cited articles. Additional materials are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eIV. \u0026nbsp; Ethics approval: Given that this meta-analysis utilized previously published data from studies that had already obtained ethics approval and consent to participate, no additional ethics approval or consent was required for this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e This study is a systematic review and meta-analysis that synthesized data from publicly available studies which had already received ethics approval and participant consent. No additional ethical approval or consent was required.\u003c/p\u003e\n\u003cp\u003eV. \u0026nbsp; \u0026nbsp;Consent to participate: Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVI. \u0026nbsp; Consent for publication: All authors have provided their consent for publication.\u003c/p\u003e\n\u003cp\u003eVII.\u0026nbsp;Code availability: At the author\u0026apos;s disposition upon reasonable request.\u003c/p\u003e\n\u003cp\u003eVIII. \u0026nbsp;Author contributions:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eo Ernesto Calderon Martinez: Conceptualization, literature search, data extraction, statistical analysis, project supervision and administration, writing, review and editing.\u003c/p\u003e\n\u003cp\u003eo Camila Sanchez Cruz: Conceptualization, project supervision and administration, writing, review and editing.\u003c/p\u003e\n\u003cp\u003eo Salma Beltran Covarrubias: Statistical analysis, writing original draft.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eo Alejandro Chen Liang: Writing original draft, general project tasks, visualization, data analysis.\u003c/p\u003e\n\u003cp\u003eo Montserrat Villa Sanchez: Writing original draft, general project tasks, visualization, data analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eo Yeison Cruz Castillo: Consensus reviewer in study selection, data extraction, methodology, writing original draft.\u003c/p\u003e\n\u003cp\u003eo Espa\u0026ntilde;a De la Rosa Valdez: Idea validation, independently selected studies, data analysis.\u003c/p\u003e\n\u003cp\u003eo Angelo Magallanes Bajana: Independently selected studies , assessment of risk of bias, data analysis.\u003c/p\u003e\n\u003cp\u003eo Frances Marie Mejia: \u0026nbsp;Reviewing and editing of original manuscript.\u003c/p\u003e\n\u003cp\u003eo Rovin Picavia: Reviewing and editing of original manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7. Statements of Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research was conducted without any external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e8. Author\u0026rsquo;s contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eS.B.C.:\u003c/strong\u003e Statistical analysis, consensus reviewer assessment of risk of bias, writing original draft.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA.M.B.:\u003c/strong\u003e Methodology, writing original draft, data analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE.D.V:\u003c/strong\u003e Idea validation, general project tasks, visualization.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA.C.L.:\u003c/strong\u003e Independently selected studies, assessment of risk of bias, writing original draft, data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eM.V.S.:\u003c/strong\u003e Independently selected studies, assessment of risk of bias, methodology, writing original draft.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eY.C.C.:\u003c/strong\u003e Consensus reviewer in study selection, data extraction, methodology, writing original draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF.M.M.:\u0026nbsp;\u003c/strong\u003eWriting \u0026amp; Editing, Supervision\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eR.P.:\u0026nbsp;\u003c/strong\u003eWriting, Review and editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC.S.C.:\u003c/strong\u003e Project supervision, assisting with general project tasks.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE.C.M.:\u003c/strong\u003e Conceptualization, literature search, data extraction, statistical analysis, project supervision and administration, writing, review and editing.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMendiratta V, Rana S, Jassi R, Chander R (May 2019) Study of causative factors and clinical patterns of periorbital pigmentation. Indian Dermatol Online J 10(3):293\u0026ndash;295. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/idoj.IDOJ_158_18\u003c/span\u003e\u003cspan address=\"10.4103/idoj.IDOJ_158_18\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHeidari F, Ebrahim Zadeh M, Haji Abole M, Zadeh, Namiranian N (2025) The Frequency of Periorbital Hyperpigmentation Risk Factors. J Cosmet Dermatol 24(2):1\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.70036\u003c/span\u003e\u003cspan address=\"10.1111/jocd.70036\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSarkar R, Ranjan R, Garg S, Garg VK, Sonthalia S, Bansal S (2016) Periorbital hyperpigmentation: A comprehensive review. J Clin Aesthetic Dermatology 9(1):49\u0026ndash;55\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChatterjee M, Suwal B, Malik A, Vasudevan B (2018) A study of epidemiological, etiological, and clinicopathological factors in periocular hyperpigmentation. Pigment Int 5(1):34. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/pigmentinternational.pigmentinternational_25_17\u003c/span\u003e\u003cspan address=\"10.4103/pigmentinternational.pigmentinternational_25_17\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRanu H, Thng S, Goh BK, Burger A, Goh CL (2011) Periorbital hyperpigmentation in Asians: An epidemiologic study and a proposed classification. Dermatol Surg 37(9):1297\u0026ndash;1303. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1524-4725.2011.02065.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1524-4725.2011.02065.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSamaan CB, Cartee TV (2023) Treatment of Periorbital Vascularity, Erythema, and Hyperpigmentation. Clin Plast Surg 50(3):399\u0026ndash;409. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.cps.2022.12.005\u003c/span\u003e\u003cspan address=\"10.1016/j.cps.2022.12.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWawrzyk-Bochenek I, Rahnama M, Stachura M, Wilczyński S, Wawrzyk A (2023) Evaluation of the Reduction of Skin Hyperpigmentation Changes under the Influence of a Preparation Containing Kojic Acid Using Hyperspectral Imaging\u0026mdash;Preliminary Study. J Clin Med 12(7). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/jcm12072710\u003c/span\u003e\u003cspan address=\"10.3390/jcm12072710\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePage MJ et al The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Mar 29 2021 BMJ Publishing Group. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmj.n71\u003c/span\u003e\u003cspan address=\"10.1136/bmj.n71\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAccessed PROSPERO May 01, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/prospero/\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/prospero/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRayyan AI-Powered Systematic Review Management Platform. Accessed: May 01, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.rayyan.ai/\u003c/span\u003e\u003cspan address=\"https://www.rayyan.ai/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eautomeris.io Computer vision assisted data extraction from charts using WebPlotDigitizer. Accessed: May 01, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://automeris.io/\u003c/span\u003e\u003cspan address=\"https://automeris.io/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRevMan Calculator | Cochrane Training. Accessed: May 01, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://training.cochrane.org/resource/revman-calculator\u003c/span\u003e\u003cspan address=\"https://training.cochrane.org/resource/revman-calculator\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHome Accessed: May 01, 2025. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.statstodo.com/index.php\u003c/span\u003e\u003cspan address=\"https://www.statstodo.com/index.php\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRevised Cochrane (2019) risk-of-bias tool for randomized trials (RoB 2)\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThe Risk Of Bias In Non-randomized Studies-of Interventions, Version 2 (ROBINS-I V2) assessment tool (for follow-up studies), 2024. [Online]. Available: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003c/span\u003e\u003cspan address=\"http://www.riskofbias.info\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchwarzer G, Carpenter JR, R\u0026uuml;cker G (2015) Meta-Analysis with R. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/978-3-319-21416-0\u003c/span\u003e\u003cspan address=\"10.1007/978-3-319-21416-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarrer M, Cuijpers P, Furukawa TA, Ebert DD (2021) Doing Meta-Analysis with R: A Hands-On Guide, \u003cem\u003eDoing Meta-Analysis with R\u003c/em\u003e, Sep. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1201/9781003107347\u003c/span\u003e\u003cspan address=\"10.1201/9781003107347\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSong Y, Sun F, Redline S, Wang R (2020) Random-effects meta-analysis of combined outcomes based on reconstructions of individual patient data, \u003cem\u003eRes Synth Methods\u003c/em\u003e, vol. 11, no. 5, p. 594, Sep. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/JRSM.1406\u003c/span\u003e\u003cspan address=\"10.1002/JRSM.1406\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHiggins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis, \u003cem\u003eStat Med\u003c/em\u003e, vol. 21, no. 11, pp. 1539\u0026ndash;1558, Jun. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/SIM.1186\u003c/span\u003e\u003cspan address=\"10.1002/SIM.1186\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeng Z, Wang J, Lin L, Wu C (Apr. 2024) Sensitivity analysis with iterative outlier detection for systematic reviews and meta-analyses. Stat Med 43(8):1549\u0026ndash;1563. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/SIM.10008\u003c/span\u003e\u003cspan address=\"10.1002/SIM.10008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEgger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Br Med J 315(7109):629\u0026ndash;634. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/BMJ.315.7109.629\u003c/span\u003e\u003cspan address=\"10.1136/BMJ.315.7109.629\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAfzal N et al (2024) Prospective randomized double-blind comparative study of topical acetyl zingerone with tetrahexyldecyl ascorbate versus tetrahexyldecyl ascorbate alone on facial photoaging. J Cosmet Dermatol 23(7):2467\u0026ndash;2477. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.16292\u003c/span\u003e\u003cspan address=\"10.1111/jocd.16292\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAhmadraji F, Shatalebi M (2015) Evaluation of the clinical efficacy and safety of an eye counter pad containing caffeine and vitamin K in emulsified Emu oil base. Adv Biomed Res 4(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/2277-9175.148292\u003c/span\u003e\u003cspan address=\"10.4103/2277-9175.148292\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAhmed NA, Mohammed SS, Fatani MI (2019) Treatment of periorbital dark circles: Comparative study of carboxy therapy vs chemical peeling vs mesotherapy. J Cosmet Dermatol 18(1):169\u0026ndash;175. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.12536\u003c/span\u003e\u003cspan address=\"10.1111/jocd.12536\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAsilian A, Amiri A, Mokhtari F, Faghihi G, Iraji F, Mozafarpoor S (2021) Platelet-rich plasma versus carboxytherapy for the treatment of periocular hyperpigmentation; which approach is superior? Dermatol Ther 34(4):0\u0026ndash;2. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/dth.14980\u003c/span\u003e\u003cspan address=\"10.1111/dth.14980\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHanan AA, Assaf A, Ahmed D (2018) Efficacy and Safety of Carboxytherapy versus Combined Microneedling with Topical Glutathione in the Treatment of Patients with Periorbital Hyperpigmentation: An EvaluatorBlind, SplitFace, Controlled Pilot Clinical Trial. Indian J Dermatol 63(2):125\u0026ndash;130. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/ijd.IJD\u003c/span\u003e\u003cspan address=\"10.4103/ijd.IJD\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBehrangi E et al (2022) Efficacy and safety of platelet-rich plasma for treatment of periorbital hyperpigmentation in patients receiving fractional CO2 laser: a parallel-group blinded randomized controlled clinical trial, \u003cem\u003eIranian Journal of Dermatology\u003c/em\u003e, vol. 25, no. 2, pp. 99\u0026ndash;105, Jun. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.22034/ijd.2021.235304.1142\u003c/span\u003e\u003cspan address=\"10.22034/ijd.2021.235304.1142\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBudania A et al (2021) Comparing novel versus conventional technique of platelet-rich plasma therapy in periorbital hyperpigmentation: A randomized prospective split-face study. J Cosmet Dermatol 20(10):3245\u0026ndash;3252. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.14121\u003c/span\u003e\u003cspan address=\"10.1111/jocd.14121\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDayal S, Sangal B, Sahu P (2020) Ferulic acid 12% peel: An innovative peel for constitutional type of periorbital melanosis\u0026mdash;Comparing clinical efficacy and safety with 20% glycolic peel and 15% lactic peel. J Cosmet Dermatol 19(9):2342\u0026ndash;2348. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.13292\u003c/span\u003e\u003cspan address=\"10.1111/jocd.13292\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDiab HM, Elhosseiny R, Bedair NI, Khorkhed AH (2022) Efficacy and safety of plasma gel versus platelet-rich plasma in periorbital rejuvenation: a comparative split-face clinical and Antera 3D camera study. Arch Dermatol Res 314(7):661\u0026ndash;671. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00403-021-02270-7\u003c/span\u003e\u003cspan address=\"10.1007/s00403-021-02270-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEl-Tahlawi SM, Fawzy MM, El Maadawi Z, Yasen SM, Aboraia NM (2022) Platelet-rich plasma versus carboxytherapy in the treatment of periorbital dark circles: A split-face study. J Cosmet Dermatol 21(10):4332\u0026ndash;4338. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.15051\u003c/span\u003e\u003cspan address=\"10.1111/jocd.15051\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEllabban NF, Eyada M, Nada H, Kamel N (2019) Efficacy and tolerability of using platelet-rich plasma versus chemical peeling in periorbital hyperpigmentation. J Cosmet Dermatol 18(6):1680\u0026ndash;1685. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.12964\u003c/span\u003e\u003cspan address=\"10.1111/jocd.12964\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFabi S et al (2023) Effectiveness of Volbella (VYC-15L) for Infraorbital Hollowing: Patient-Reported Outcomes from a Prospective, Multicenter, Single-Blind, Randomized, Controlled Study, \u003cem\u003eAesthet Surg J\u003c/em\u003e, vol. 43, no. 11, pp. 1357\u0026ndash;1366, Nov. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/asj/sjad100\u003c/span\u003e\u003cspan address=\"10.1093/asj/sjad100\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGhandehari R, Robati RM, Niknezhad N, Hajizadeh N, Tehranchinia Z (2022) Efficacy and safety of fractional CO2 laser and tranexamic acid versus microneedling and tranexamic acid in the treatment of infraorbital hyperpigmentation. J Dermatological Treat 33(3):1391\u0026ndash;1396. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/09546634.2020.1819527\u003c/span\u003e\u003cspan address=\"10.1080/09546634.2020.1819527\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHamdi H et al (2023) Evaluation of the Effect of Artemisia Absinthium L. Eye-Cream on Infra-Orbital Dark Circle: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. GMJ 12:2413. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.31661/gmj.v12i0.2413\u003c/span\u003e\u003cspan address=\"10.31661/gmj.v12i0.2413\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIranmanesh B, Rastaghi F, Hashemi NS, Kaveh R (2024) Comparison of the Effectiveness of Platelet-Rich Plasma Versus Tranexamic Acid Plus Vitamin C Mesotherapy in the Treatment of Periorbital Hyperpigmentation: A Split-Site, Randomized Clinical Trial. J Cosmet Dermatol 23(12):4066\u0026ndash;4071. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.16548\u003c/span\u003e\u003cspan address=\"10.1111/jocd.16548\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKadry A, Gamal A, Alkhalifah A, Ibrahim SMA (2023) Efficacy of Platelet-Rich Plasma Versus Autologous Fat Transfer With Nanofat in the Treatment of Infraorbital Dark Circles: A Single-Blinded Randomized Comparative Clinical Trial. Dermatol Surg 49(3):247\u0026ndash;252. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/DSS.0000000000003697\u003c/span\u003e\u003cspan address=\"10.1097/DSS.0000000000003697\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKhan I, Nasr N, Habib A, Jabin I, Iram S, Iram S (2023) Comparison of Carboxy Therapy and Platelet-Rich Plasma Therapy in Patients With Periorbital Hyperpigmentation. J Popul Ther Clin Pharmacol 30(1):2259\u0026ndash;2265. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.53555/jptcp.v30i17.2943\u003c/span\u003e\u003cspan address=\"10.53555/jptcp.v30i17.2943\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLu Y et al (2025) Platelet-Rich Plasma Injection Combined With Q-Switched Ruby Laser in the Treatment of Periorbital Hyperpigmentation. J Cosmet Dermatol 24(1):1\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.16598\u003c/span\u003e\u003cspan address=\"10.1111/jocd.16598\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNilforoushzadeh MA et al (2021) Assessing the effectiveness of the combination therapy with fractional Er-YAG laser and platelet-rich plasma in treatment of periorbital dark circles patients: A clinical trial. J Cosmet Dermatol 20(11):3526\u0026ndash;3536. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.14036\u003c/span\u003e\u003cspan address=\"10.1111/jocd.14036\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNilforoushzadeh MA, Heidari-Kharaji M, Alavi S, Zolghadr S, Mahmoudbeyk M, Nikkhah N (2021) Comparison of carboxy therapy and fractional Q-switched ND:YAG laser on periorbital dark circles treatment: a clinical trial. Lasers Med Sci 36(9):1927\u0026ndash;1934. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10103-021-03274-5\u003c/span\u003e\u003cspan address=\"10.1007/s10103-021-03274-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNofal E, Elkot R, Nofal A, Eldesoky F, Shehata S, Sami M (2018) Evaluation of carboxytherapy and platelet-rich plasma in treatment of periorbital hyperpigmentation: A comparative clinical trial. J Cosmet Dermatol 17(6):1000\u0026ndash;1007. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.12478\u003c/span\u003e\u003cspan address=\"10.1111/jocd.12478\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOhshima H et al (2009) Effects of vitamin C on dark circles of the lower eyelids: Quantitative evaluation using image analysis and echogram. Skin Res Technol 15(2):214\u0026ndash;217. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1600-0846.2009.00356.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1600-0846.2009.00356.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNann Phoo TS, PHOO MON1, THE EFFICACY OF 2% Andrographis paniculata EXTRACT CREAM IN REDUCING PERIORBITAL WRINKLES AND HYPERPIGMENTATION (2025), vol. 3, no. 3, pp. 3\u0026ndash;4\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRanjan R, Sarkar R, Garg V, Gupta T (2016) A comparative study of two modalities, 4% hydroquinone versus 30% salicylic acid in periorbital hyperpigmentation and assessment of quality of life before and after treatment, \u003cem\u003eIndian J Dermatol\u003c/em\u003e, vol. 61, no. 4, pp. 413\u0026ndash;417, Jul. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/0019-5154.185707\u003c/span\u003e\u003cspan address=\"10.4103/0019-5154.185707\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoohaninasab M et al (2024) The investigation and comparison of the efficacy and safety of stromal vascular fraction (SVF), platelet rich plasma (PRP), and 1064-nm Q-switched Nd:YAG laser in reducing nanofat treated infraorbital dark circles and wrinkles: A controlled blinded random. Skin Res Technol 30(6):1\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/srt.13793\u003c/span\u003e\u003cspan address=\"10.1111/srt.13793\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoshdy OH, Abd Elall HM, Eid AA (2022) A randomized comparative study of the effect of two different flow rates of carboxytherapy in the treatment of infraorbital dark circles. J Cosmet Dermatol 21(9):4020\u0026ndash;4027. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.14714\u003c/span\u003e\u003cspan address=\"10.1111/jocd.14714\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMohamed Shalash A, Moustafa Fawzy M, Naiem Elfar N, Ramzy Ghaly N (Jan. 2023) Comparison between Efficacy of Carboxytherapy, Plasma Gel Injection and Mesotherapy in Treatment of Periorbital Dark Circles. J Adv Med Med Res 8\u0026ndash;17. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.9734/jammr/2023/v35i24939\u003c/span\u003e\u003cspan address=\"10.9734/jammr/2023/v35i24939\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWu X, Liu Y, Zhu J, Yu W, Lin X (2022) A Prospective Trial of the Microneedle Fractional Radiofrequency System Application in the Treatment of Infraorbital Dark Circles. Clin Cosmet Investig Dermatol 15:1293\u0026ndash;1300. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/CCID.S372409\u003c/span\u003e\u003cspan address=\"10.2147/CCID.S372409\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYu CQ, Xu XG, Chen HD, Li YH (2021) Clinical efficacy and safety of nano-microneedle-assisted phenylethyl resorcinol for the treatment of infraorbital dark circles. J Cosmet Dermatol 20(3):884\u0026ndash;889. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.13641\u003c/span\u003e\u003cspan address=\"10.1111/jocd.13641\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZaheri H, Beyzaee AM, Rokni GR, Patil A, Golpour M, Goldust M (2023) Comparison of the efficacy of carboxytherapy versus fractional CO2 laser therapy for the treatment of periorbital dark circles: A randomized clinical trial. J Cosmet Dermatol 22(2):512\u0026ndash;516. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jocd.15337\u003c/span\u003e\u003cspan address=\"10.1111/jocd.15337\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZamanian A, Azizi M, Ghasemi M, Behrangi E, Naeji S (2019) Comparing the effectiveness of fractional CO 2 laser and the combination therapy with micro-needling and topical 10% trichloroacetic acid to remove infra-orbital dark circles in Tehran women. J Cosmet Laser Therapy 21(2):61\u0026ndash;64. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/14764172.2017.1341047\u003c/span\u003e\u003cspan address=\"10.1080/14764172.2017.1341047\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePour Mohammad A, Zeinali R, Jafary P, Mortaja M, Jafarzadeh A, Goodarzi A (2025) The First Systematic Review and Meta-Analysis of Pharmacological and Nonpharmacological Procedural Treatments of Dark Eye Circles (Periorbital Hyperpigmentations): One of the Most Common Cosmetic Concerns, \u003cem\u003eDermatol Ther\u003c/em\u003e, vol. no. 1, 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/dth/9155535\u003c/span\u003e\u003cspan address=\"10.1155/dth/9155535\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSeirafianpour F et al (2024) Effectiveness, safety, and patient satisfaction of carboxytherapy as an adjunctive treatment for periorbital hyperpigmentation. Skin Res Technol 30(3):1\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/srt.13651\u003c/span\u003e\u003cspan address=\"10.1111/srt.13651\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-dermatological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Archives of Dermatological Research](https://www.springer.com/journal/403)","snPcode":"403","submissionUrl":"https://submission.nature.com/new-submission/403/3","title":"Archives of Dermatological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"VAS scores, Periorbital hyperpigmentation, Carboxytherapy, Platelet-rich plasma (PRP), Pigmentation, Erythema, Patient satisfaction","lastPublishedDoi":"10.21203/rs.3.rs-7537721/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7537721/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground:\u003c/p\u003e\n\u003cp\u003ePeriorbital hyperpigmentation (POH) is a common cosmetic concern characterized by bilateral darkening around the eyes, impacting quality of life. Classified as pigmented, vascular, and structural. Treatments include non-invasive treatments encompass topical agents and lasers, while invasive options include fillers or surgery. Despite a standardized guideline, this study synthesizes current evidence to identify the most effective therapies, evidence-based strategies for optimal POH management.\u003c/p\u003e\n\u003cp\u003eMethods:\u003c/p\u003e\n\u003cp\u003eFollowing PRISMA guidelines and registering this review in PROSPERO (CRD420251082683), six databases were searched through June 2025 including randomized controlled trials of periorbital hyperpigmentation therapies. Primary outcomes include dermatologist assessments, pigmentation grading scales, patient-reported satisfaction and studies reporting response categories (e.g., excellent or good). Secondary outcomes will include adverse events as erythema. Random-effects models were used to calculate pooled effect sizes. Risk of bias was assessed using the Cochrane Rob 2.0 tool for randomized controlled trials (RCTs) and the ROBINS-I V2 tool for non-randomized controlled trials.\u003c/p\u003e\n\u003cp\u003eResults:\u003c/p\u003e\n\u003cp\u003eThirty-one studies (n = 1,257) met inclusion criteria. Clinical improvement was assessed by dermatologist evaluation as “good” (\u0026gt;50%) and “excellent” (\u0026gt;75%). Carboxytherapy achieved the highest pooled rate of good improvement 0.50 (95% CI: 0.27 to 0.73; I² = 74.8%), and of excellent improvement 0.26 (95% CI: 0.17 to 0.37; I² = 15.3%). Carboxytherapy also was associated with notable reductions in VAS scores (4.69; 95% CI: 3.97 to 5.40; I² = 67.4%), melanin index reduction (75.23; 95% CI: 23.41 to 127.04; I² = 97.7%) and the lowest pooled value for erythema index (41.09 (95% CI: 28.58 to 53.60). For patient satisfaction carboxytherapy consistently yielded the highest rate of good satisfaction (0.52; 95% CI: 0.38–0.66; I² = 32.8%), whereas carboxytherapy (0.21, 95% CI: 0.07 to 0.47; I² = 56.4%) and PRP consistently achieved an excellent satisfaction (0.18; 95% CI: 0.11–0.28; I² = 0.00%).\u003c/p\u003e\n\u003cp\u003eConclusion:\u003c/p\u003e\n\u003cp\u003eCarboxytherapy and PRP improve clinical efficacy and patient satisfaction in POH by effectively reducing pigmentation and erythema with favorable safety profiles. However, study heterogeneity and lack of standardized subtype classifications limit conclusions. Well-designed, standardized trials are essential to optimize treatment protocols and confirm the long-term safety.\u003c/p\u003e","manuscriptTitle":"Treatments in Periorbital Hyperpigmentation: A Systematic Review and Single-Arm Meta- Analysis of Clinical Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-20 08:14:26","doi":"10.21203/rs.3.rs-7537721/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-15T17:29:22+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"206176018872247719410333718546962401539","date":"2026-01-10T20:14:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18291654491966926690508782292703064016","date":"2026-01-10T04:14:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-08T05:52:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"201828613461474662883663225058534750999","date":"2026-01-07T23:09:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-07T01:11:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"140899274670152825702257993479031769637","date":"2026-01-07T01:03:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"125378892415925743618160120789532190050","date":"2026-01-06T16:56:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"27296474603814757607096425608301902599","date":"2026-01-05T20:17:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-01T16:57:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"221231464391395917727589143809992744514","date":"2025-11-26T08:01:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"71005836273724229623093053268463674231","date":"2025-11-19T15:35:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-19T13:49:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6972950482004056909269777949738233232","date":"2025-11-10T20:01:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-10T16:48:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-05T09:04:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-05T09:04:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Dermatological Research","date":"2025-09-04T15:35:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-dermatological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Archives of Dermatological Research](https://www.springer.com/journal/403)","snPcode":"403","submissionUrl":"https://submission.nature.com/new-submission/403/3","title":"Archives of Dermatological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2b9af4b2-8d87-4111-9fc7-222ba37ff57c","owner":[],"postedDate":"November 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-27T17:38:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-20 08:14:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7537721","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7537721","identity":"rs-7537721","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}