Bibliometric and visual analysis on oxidative stress in gynecological and reproductive diseases: A systematic review.

Reactive oxygen species (ROS) are byproducts of normal aerobic metabolism and serve a vital physiological function at low to moderate concentrations. [ 1 ] Oxidative stress (OS) is characterized as an imbalance in ROS production coupled with a decline in cellular antioxidant capacity, leading to damage the biomolecules, cells, tissues, and organs. [ 2 , 3 ] OS plays a role in a multitude of diseases, including those affecting the neurological, cardiovascular, and digestive systems. Additionally, research has established that OS contributes to gynecological and reproductive disorders. For instance, it is implicated in the onset and progression of female reproductive-related diseases such as polycystic ovary syndrome (PCOS), endometriosis (EMs), recurrent spontaneous abortion, and various pregnancy diseases. It also has close relationship with prognosis of these diseases. [ 4 ] Concurrently, OS can detrimentally impact semen quality and male reproductive function. [ 5 , 6 ] Bibliometric analysis is a widely employed technique for examining a substantial volume of publications using mathematical and statistics methods, revealing details about institutions, citations, journals and keywords. The visualization programs CiteSpace and VOSviewer are frequently used for large-scale data analysis. [ 7 – 9 ] Leveraging their robust data analysis capabilities and advanced graphic features, these tools enable the clear and direct identification and presentation of a significant number of articles. They facilitate the rapid identification of hotspots and trends in specific areas, providing valuable insights for future research. Overall, these tools effectively meet the requirements of researchers analyzing articles in burgeoning fields. To summarize, OS in gynecological and reproductive diseases has attracted significant attention, as evidenced by the extensive volume of literature. However, the sheer number of articles complicates the extraction of key insights, and a deficiency in focused research on prevailing topics could impede future advancements in this area. Bibliometric analysis serves as a crucial method for both qualitative and quantitative article evaluation. Tools like VOSviewer and CiteSpace are commonly utilized for identifying research trends. In this study, articles pertaining to OS in gynecology and reproductive diseases were sourced from the Web of Science Core Collection (WoSCC) database. A comprehensive analysis was conducted to uncover global trends and frontiers, thereby offering robust evidence and direction for subsequent research in this domain.

Formal analysis: Ling Wang. Funding acquisition: Liuqing Yang, Qin Zhang. Investigation: Ling Wang. Methodology: Sichen Yang, Xiaoxuan Zhao, Qin Zhang. Project administration: Xiaona Ma, Jing Ma. Resources: Jing Ma. Supervision: Xiaona Ma, Liuqing Yang, Jing Ma, Qin Zhang. Visualization: Sichen Yang, Xiaona Ma. Writing – original draft: Ling Wang, Sichen Yang. Writing – review & editing: Liuqing Yang, Xiaoxuan Zhao, Qin Zhang.

The article search was conducted in the WoSCC database on September 13, 2022. The employed search strategy was as follows: ((WC = (Obstetrics & Gynecology)) AND WC = (Reproductive Biology)) AND TS = (reactive oxygen species OR oxidative stress). Only articles and reviews written in English were included in this study (Fig. 1 ). Flow chart of literature collecting. Two researchers independently reviewed each article to ensure relevance to the field. Microsoft Office Excel 2019 was used to create a line chart depicting the publication trend. Subsequently, the online analysis platform of bibliometrics ( http://bibliometric.com/ ) was used to analyze publication trends and cooperation across different countries/regions. All eligible articles were imported into the CiteSpace software V6.1R3 SE by using the following parameters: time span (2008–2022), years per slice (1), top N per slice (50), node type (selected one at a time), and pruning (pathfinder and pruning sliced networks) were the parameters that were established. “Keywords” were chosen as the Node Type accordingly. VOSviewer 1.6.18 was utilized to map the authors, institutions, countries/regions, and collaborative linkages of highly co-cited references and their co-occurrence.

A total of 1423 articles were published on WoSCC between 2008 and 2022 (Fig. 2 A). During these 15 years, research on OS in gynecological and reproductive diseases remained a highly active area. The data revealed that the number of publications fluctuated, reaching a peak in 2021. To identify dominant countries or regions in this field, further analysis was conducted. The bar chart displays the top 10 countries/regions by total publication count over the past 15 years (Fig. 2 B). Undoubtedly, the USA was the leading contributor. However, annual publications in China were increasing rapidly, eventually surpassing the USA in early 2020. Publication trend. (A) The changing trend of the annual publication. (B) The changing trend of the annual publication in the top 10 countries/regions. [Export of results from the Online Analysis Platform of Literature Metrology ( http://bibliometric.com )]. From 2008 to 2022, at least 51 countries/regions participated the research in this field (Fig. 3 ). The highest number of publications was in the USA (375, 26.1%), followed by China (198, 13.9%), the UK (110, 7.73%), Australia (104, 7.31%), and Brazil (93, 6.54%). However, Figure 2 indicated a lack of communication between these countries. In the institutional analysis, a total of 1688 institutions included, with the top 2 being from the USA: Cleveland Clinic (n = 67) and Wayne State University (n = 52), followed by Newcastle University (n = 47) from Australia (Table 1 ). The USA not only had the highest number of publications but also the most citations. This underscores the USA’s predominant role in this field. Top 10 productive countries/regions and institutions. The international collaborations’ map of countries/regions and the thickness of the line between countries reflects the frequency of the cooperation. These 1423 publications spanned 15 journals, with the top 10 journals accounting for the majority of publications. PLACENTA, with an impact factor (IF) of 3.481, was the leading journal, contributing to 26.1% of publications (Table 2 ). It was followed by FERTILITY AND STERILITY (IF = 7.490) and REPRODUCTIVE SCIENCES (IF = 2.924), with 198 and 110 publications, respectively. Moreover, the journals with the highest number of citations were FERTILITY AND STERILITY (670 citations), PLACENTA (421 citations), and HUMAN REPRODUCTION (395 citations). Notably, half of these journals were based in England, with the others from the USA, Netherlands, Germany, and Ireland. The IF scores of the top 10 journals ranged from 2.186 to 17.179, with 30% of them from Quartile 1. This indicates that these journals provide a solid foundation for further comprehensive research on OS in gynecological and reproductive diseases. Top 10 productive journals. A total of 6925 authors involved in this field, with Table 3 listing the top 10 authors who made significant contributions. Agarwal A, from the Cleveland Clinic in the USA, was the most prolific author, publishing 43 articles, followed by Aitken RJ from Newcastle University in Australia. Ranking third was Sharma R, also from the Cleveland Clinic. Meanwhile, Agarwal A and Aitken RJ were the top 2 co-cited authors. Many researchers have made substantial contributions over the past 15 years (Figure S1, Supplemental Digital Content, http://links.lww.com/MD/M190 ). Top 10 productive authors and cited authors. The co-citation analysis was completed, revealing connections when 2 or more authors are cited simultaneously. This analysis provides a clear understanding of the leading authors and their contributions to the field, as depicted in Figure S2, Supplemental Digital Content, http://links.lww.com/MD/M191 and Figure S3, Supplemental Digital Content, http://links.lww.com/MD/M192 . The node size indicates each author’s level of involvement, with each line representing a citation and the thickness denoting citation frequency. The results show that 4 authors had received more than 200 citations, with Agarwal A was the most co-cited author (812 times). Keywords succinctly encapsulate and accurately reflect the themes of articles. Co-word analysis is employed to identify research hotspots by analyzing the frequency and correlation of keywords. Therefore, an evaluation of high-frequency keywords was performed to highlight research hotspots and critical issues. Excluding keywords lacking referential significance, the top 10 most frequent keywords included “oxidative stress,” “expression,” “male infertility,” “women,” “in vitro fertilization,” “pregnancy,” “human spermatozoa,” “DNA damage,” “gene expression,” and “in vitro” (Fig. 4 A). Map based on CiteSpace. (A) Keyword co-occuruence map. (B) Keywords clustering analysis map. The keyword co-occurrence analysis involves quantifying the frequency of keyword appearances in a specific field and assessing the connections and degree of association between these terms. To discern core topics, further clustering and analysis of keywords were undertaken. Similar terms were sorted into the same cluster, and cluster labels were generated using a minor square filtering algorithm, extracting prominent noun phrases from the keywords. This process categorized the hotspots into various groups, revealing that “placenta,” “PCOS,” “male infertility,” and “oocyte quality” were the key points (Fig. 4 B). A timeline viewer shows the historical process of the research, which presents stage characteristics of a certain field. According to the CiteSpace parameters, Figure 5 intuitively shows the phased hotspots and development directions of this field. The network was obtained with 488 nodes, 4330 connections, and 0.0346 density, suggesting the cluster is well-defined. The nodes with different sizes on the timeline represent some keywords with a high citation frequency. From 2008 to 2015, the research mainly focused on the types and influencing factors of OS-related diseases, such as male infertility, PCOS, and EMs. From 2016 to 2022, more research was involved in antioxidant therapy, disease management, and OS markers. CiteSpace visualization map of timeline viewer. Burst keyword detection was conducted using CiteSpace. Keyword burstness acts as an indicator of emerging academic trends and topics, forecasting future research directions and hotspots. The start year, end year, and duration of the burst were represented by the red section, while the entire timeline was in blue. A total of 25 prominent keywords were identified (Fig. 6 ). “Body mass index” exhibited the highest burst strength, followed by “plasma” and “chromatin structure assay.” Over these 15 years, “oxygen” consistently remained a focus. However, “Human spermatozoa,” “peritoneal fluid,” and “free radical” demonstrated shorter durations of prominence. Additionally, it showed that research on these keywords, like “oocyte quality” (burst strength 4.91), “metabolism” (burst strength 3.97), “inflammation” (burst strength 5.4), “supplementation” (burst strength 5.12) and “pathogenesis” (burst strength 4.23) had been persistently topical in recent years. CiteSpace visualization map of top 25 keywords with the strongest citation bursts.

OS is defined as an imbalance between the generation and scavenging of ROS. To date, the influence of OS on various physiological systems has been extensively documented, [ 10 – 13 ] particularly within the reproductive system. [ 14 – 16 ] There has been a substantial volume of research on OS in the context of gynecological and reproductive diseases, with numerous findings being broadly disseminated. Consequently, there is a marked interest in examining the current landscape and trends of this topic. This study conducted an in-depth bibliometric analysis to delineate the present state and key areas of interest in OS pertaining to gynecological and reproductive diseases. This study visualized the research characteristics in this field from 2008 to 2022. The USA and China contributed the most publications. Over these 15 years, the annual number of publications remained consistent in many countries, including the USA and UK. However, a rapid increase in the volume of publications was observed in China, accounting for a significant proportion in recent years. Institutions from the USA and Australia have made substantial contributions. The USA has been particularly notable for its outstanding contributions in terms of the number of publications, citations, and institutions. Nevertheless, the international collaborations map indicated a lack of cooperation among countries, hindering efficient sharing of research results, which may impede progress in the field. Enhanced international cooperation could lead to more significant advancements in this area of research. The journal PLACENTA published 250 papers in this field, followed by FERTILITY AND STERILITY and REPRODUCTIVE SCIENCES. Among all publications, a review from HUMAN REPRODUCTION UPDATE illustrated the relationship between ROS and infertility received the highest citations. [ 17 ] Besides, another review published on PLACENTA about the influence of OS on the placenta also had a significant academic impact. [ 18 ] This suggests that future developments are likely to be featured in these journals. However, most journals did not possess high IF scores, indicating a need for more high-quality research. In terms of author and coauthor analysis, more than half of the highly prospective authors were from the USA, predominantly affiliated with Cleveland Clinic and Newcastle University. This illustrates a strong interconnection among authors, institutions, and countries are interconnected. Agarwal A, Aitken RJ, and Sharma R, the most contributing authors, focused on male infertility. Agarwal A, as early as 1996, proposed the link between male infertility and ROS. He proposed that some metabolites, such as H 2 O 2 and the superoxide anion could cause oxidative damage from ROS, and posited ROS as a key factor in sperm function issues in male infertility. He advocated for precise evaluation of ROS levels and subsequent OS to assist clinicians in understanding fertility issues. [ 19 ] In a later investigation, he measured oxidative reduction potential levels in the semen and seminal plasma of fertile and infertile males using proprietary technology, establishing a healthy reference range. [ 20 ] He also confirmed the effects of exogenous antioxidants on male infertility. [ 21 ] Aitken RJ also contributed significantly to the understanding of infertility and OS, [ 22 ] elucidating the molecular pathways of sperm OS. [ 23 ] Sharma R’s contributions included advancing methods for detecting sperm OS levels. [ 24 ] He proposed that an adequate antioxidant defense mechanism could protect sperm proteins in men with high ROS levels, suggesting that antioxidant therapy could improve male infertility. [ 25 ] Our results indicate that the primary hotspots of OS in gynecological and reproductive diseases as male infertility, PCOS, EMs, and oocyte quality. Infertility affects 8% to 12% of couples in the worldwide, with nearly 50% attributable to male factors. Among these, 30% to 80% are due to ROS-mediated sperm damage. [ 26 ] While an optimal level of ROS is necessary for sperm physiological processes such as capacitation, hyperactivation, and the acrosome reaction, [ 27 ] excessive ROS generation can occur due to various factors including reproductive infections, varicocele, smoking, alcohol, drugs, radiation, stress, strenuous exercise, spinal cord injury, and environmental pollution. [ 28 , 29 ] OS can lead to enzyme inactivation and protein oxidation in sperm, accelerating germ cell apoptosi. This, in turn, may result in poor embryo quality, reduced implantation rates, and increased pregnancy loss. [ 30 – 35 ] Antioxidants play a crucial role in neutralizing ROS. Various antioxidants have been used to treatment of male infertility, such as folic acid, zinc, vitamin E, carnitine, selenium, coenzyme Q10 (CoQ10), N-acetylcysteine, methionol, and melatonin. Studies have shown that antioxidants improve sperm concentration and motility, reduce OS damage and sperm DNA fragmentation, and enhance fertilization and pregnancy rates. [ 36 – 39 ] Different antioxidants serve specific functions, for example, CoQ10 and l-carnitine aid sperm motility and concentration, while vitamin C improves sperm morphology. [ 40 , 41 ] In vitro studies suggest that OS is a primary factor affecting the survival and fertilization capacity of cryopreserved sperm. During assisted reproductive technology procedures, factors such as exposure to visible light, centrifugation, cryopreservation, medium composition, O2 tension, PH value, and temperature can induce OS, adversely affecting sperm quality. [ 42 ] Incorporating antioxidants into the medium may offer a potential solution, [ 43 , 44 ] but further high-quality evidence is needed. In females, OS also plays a significant role, being linked to various diseases such as PCOS, EMs, pregnancy loss, and infertility. [ 45 ] PCOS, a prevalent gynecological endocrine disorder, affects 5% to 20% of women of reproductive age globally. [ 46 ] Uyanikoglu et al [ 47 ] found that women with PCOS exhibit higher levels of total oxidants, antioxidants, and OS index compared to the general population, suggesting the occurrence of OS. Papalou et al [ 48 ] described PCOS as essentially an oxidative condition. OS is implicated in various clinical manifestations of PCOS, including hyperandrogenism, obesity, and insulin resistance. [ 49 ] It also influences the intrauterine environment during pregnancy, leading to adverse pregnancy outcomes. [ 50 ] Clinical evidence has demonstrated that antioxidant therapy significantly affects lipid metabolism and insulin resistance. However, it has shown no marked effect on body mass index, testosterone levels, or pregnancy rates. [ 51 , 52 ] OS is also implicated in EMs. EMs involves the dispersion of vascularized endometrioid glandular tissue in ectopic sites outside the uterus, causing severe primary dysmenorrhea, chronic pelvic pain, difficulties during sexual intercourse, and infertility. [ 53 ] Worldwide, 5% to 15% of women are affected by EMs, with a prevalence rate of 30% to 45% among those with infertility. The etiology and mechanisms of EMs remain largely elusive. However, the potential role of OS in the pathogenesis of EMs has garnered significant attention. Studies have shown elevated levels of ROS in serum, follicular fluid, ovarian cortex, endometrial tissue, and peritoneal fluid in women with EMs, whereas the levels of superoxide dismutase (SOD), glutathione peroxidase, and total antioxidant capacity are reduced. [ 54 – 57 ] Ng et al [ 58 ] found that in vitro, oxygen ions affect both ectopic endometrial stromal cells and ectopic intima epithelial cells, with SOD playing a crucial role in decomposing oxygen ions to maintain OS balance. Moreover, SOD has been found to protected oocytes from damage caused by high levels of ROS, thereby enhancing the success rate of assisted reproductive technology. [ 59 ] In case of ovarian EMs, SOD2 is instrumental in facilitating cell migration and proliferation. [ 60 ] Some researchers proposed that OS could be used as a predictor of the progress of EMs. [ 61 ] Antioxidant therapy emerges as a potential treatment, effectively reducing the severity of dysmenorrhea, alleviating sexual and pelvic pain, diminishing endometrial cyst volume, inhibiting cell proliferation, migration, and invasion of endometrial tissue, reducing fibrosis markers, and preventing fibrosis progression. [ 62 , 63 ] ROS are related in various germ cell development processes as well, such as ovarian steroidogenesis, oocyte maturation, ovulation, blastocyst formation, implantation, luteolysis, and luteal maintenance during pregnancy. [ 64 , 65 ] OS can damage cell membrane lipids and DNA, induce apoptosis in granulosa cells and oocytes, lead to atresia of follicles, inhibit fertilization and ATPase activity, and damage mitochondria, ultimately affecting embryonic development. [ 66 ] The addition of antioxidants like melatonin, CoQ10, and quercetin, to the culture medium of oocytes in vitro can improve the quality of thawed oocytes, as well as promote oocyte maturation and subsequent embryonic development. [ 67 – 69 ] Moreover, studies indicate that OS contributes to decreased ovarian function. Age-related oxidative damage in the body escalates with a decline in antioxidant enzyme expression, resulting in deterioration of lipids, proteins, DNA, and other components in ovarian tissue and granulosa cells. [ 70 , 71 ] OS has been observed in aged human and mouse ovaries, as well as in human granulosa cells, cumulus cells, where antioxidants have demonstrated potential to ameliorate these effects. [ 72 ] This study presents the most up-to-date research characteristics of OS in gynecological and reproductive diseases, introducing new perspectives. However, it is not without limitations. Firstly, ensure accessibility and comprehension among academics from diverse countries, only English-language publications were included, potentially overlooking relevant research in other languages. Secondly, the reliance on a single database may constrain the breadth of our findings. In the future, we aim to conduct a more comprehensive search encompassing a wider range of studies on OS in gynecological and reproductive diseases, covering an extended period.

This study delineates current research characteristics and trends in OS within gynecological and reproductive diseases through bibliometric analysis. Predominantly, the research mainly focuses on male infertility, in vitro fertilization, oocyte quality, and metabolism. These findings are valuable for researchers, guiding them in determining future research directions and assisting in the identification and resolution of potential challenges.

We thank all staff who devoted their time and efforts to the study.