We are pleased to introduce the collection Frontiers in Reproductive Health – Highlights in Gynecology 2021/22. This collection will welcome and showcase a selection of high impact articles authored by leaders in the field. The work presented here highlights the broad diversity of research performed across the Gynecology section, and aims to put a spotlight on the main areas of interest. This collection aims to further support Frontiers’ strong community by shining a spotlight on our authors' highly impactful research.

University of Edinburgh

Unit of Gynecology, Department of Woman-Child-Newborn, IRCCS Ca 'Granda Foundation Maggiore Policlinico Hospital

Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, Medical Sciences Division, University of Oxford

Exploring the broad diversity of research across Gynecology and highlighting authors' impactful work.

. This research topic focuses on the effects of endometriosis and related conditions on reproductive-age women. The findings of the studies include: <ul> <li>Synthetic cannabinoid WIN 55212-2 (WIN 55) reduced proliferation and inflammation in endometriosis-representative in vitro and in vivo syngeneic mouse models.</li> <li>Pathophysiologic mechanisms of extrapelvic musculoskeletal endometriosis and the role of musculoskeletal trauma in its development are discussed.</li> <li>Hispanic/Latinx endometriosis patients from Latin America and Spain have higher prevalence and severity of dysmenorrhea and dyspareunia and high levels of pain catastrophizing.</li> <li>The pooled prevalence of polycystic ovary syndrome (PCOS), endometriosis, uterine fibroids, and adenomyosis in women of Middle Eastern origin is 8.9%, 12.9%, 30.6%, and 30%, respectively.</li> </ul>

Frontiers in Reproductive Health

Gynecology

Highlights in Gynecology 2021/22

Editorial on the Research Topic <a href="https://www.frontiersin.org/research-topics/33568/highlights-in-gynecology-202122">Highlights in gynecology 2021/22</a>In this Frontiers in Reproductive Health Research Topic entitled &#x201c;Highlights in Gynecology 2021/2022&#x201d;, we present a collection of papers focusing on global themes central to women&apos;s health. This collection aims to highlight the broad diversity of research performed across the Gynecology section and to spotlight the main areas of interest. In addition, this Editorial introduces three manuscripts published as a collection in response to the above-mentioned Research Topic.- Summary of “Prevalence of Common Gynecological Conditions in the Middle East: Systematic Review and Meta-Analysis” (<a href="https://doi.org/10.3389/frph.2021.661360">Mousa et al.</a>)<a href="https://doi.org/10.3389/frph.2021.661360"></a>This systematic review critically assesses the evidence from epidemiological research and performs a meta-analysis of studies estimating the prevalence of endometriosis, polycystic ovary syndrome (PCOS), uterine fibroids, and adenomyosis in Middle Eastern populations. Most studies from the region have low sample sizes and there are inconsistencies in terms of the methodology and representativeness of the study samples; therefore, a meta-analysis of the available evidence from these studies represents a valuable contribution to the literature. The authors conclude that the pooled prevalence of PCOS diagnosed according to NIH criteria is 8.9% (range, 4%–27.6%), with the highest prevalence (18.8%) observed in the Gulf Arab states (range, 12.1%–27.6%). The prevalence of endometriosis is limited to women undergoing laparoscopic surgery (12.9%; range, 4.2%–21%), and the prevalence of adenomyosis in women undergoing hysterectomy is 30.8% (range, 25.6%–37.7%). The prevalence of uterine fibroids is estimated to be 28.2% overall in the region (range, 18.5%–42.6%) and 57.1% among women with heavy menstrual bleeding. The authors highlight the potential health disparities in these populations and call for further research to understand the regional environmental and genetic risk factors for these conditions.- Summary of “Ibero-American Endometriosis Patient Phenome: Demographics, Obstetric-Gynecologic Traits, and Symptomatology” (<a href="https://doi.org/10.3389/frph.2021.667345">Flores-Caldera et al.</a>)In this cross-sectional study, the authors collect self-reported data on the demographics, lifestyle, and endometriosis symptoms of Hispanic/Latinx endometriosis patients from April 2019 to February 2020. In general, Hispanic/Latinx individuals with endometriosis are underrepresented in research databases and are thus unlikely to benefit from any advancements in pathophysiology, biomarkers, and novel treatments. To fill this knowledge gap, <a href="https://doi.org/10.3389/frph.2021.667345">Flores-Caldera et al.</a> for the first time in the literature, define the clinical profile of endometriosis patients from Latin America and the Caribbean using a Spanish translation of EPHect's Minimal Clinical Questionnaire (EPQ-M). A total of 1,378 individuals from 23 countries answered the questionnaire. Patients were recruited through collaborations with patient associations in South America, Central America, the Caribbean, and Spain. This study represents the first attempt to generate a clinical-demographic profile of Hispanic/Latinx endometriosis patients. The survey results suggest that, compared with other cohorts, Hispanic/Latinx endometriosis patients reported a higher prevalence and severity of dysmenorrhea and dyspareunia and high levels of pain catastrophizing.- Summary of “Case Report: Extrapelvic Endometriosis in the Medial Thigh” (<a href="https://doi.org/10.3389/frph.2021.692249">Pascoal et al.</a>)<a href="https://doi.org/10.3389/frph.2021.692249">Pascoal et al.</a> present the case of a 39-year-old nulliparous woman with a rare form of extrapelvic musculoskeletal endometriosis in the medial thigh. Extrapelvic musculoskeletal endometriosis is a rare entity with likely multifactorial pathogenesis. Interestingly, the patient had a history of pelvic fractures. The authors formulate a possible fascinating pathogenic theory for the insurgence of extrapelvic endometriosis based on the stem/progenitor cell theory and the role that musculoskeletal trauma may have in the development of this condition. In addition, the authors explore the various management options for this rare form of the disease and suggest a multidisciplinary approach to ensure optimal margins and minimize morbidity secondary to surgical resection and defect closure.<a href="https://doi.org/10.3389/frph.2021.661360">Both Mousa et al.</a> and <a href="https://doi.org/10.3389/frph.2021.667345">Flores-Caldera et al.</a> present epidemiological insights into common gynecological conditions in underrepresented populations in women's health. These valuable contributions are important for highlighting potential health disparities and the need to expand the basis of gynecological research to diverse populations to better understand the population-specific environmental and genetic risk factors. Lastly, <a href="https://doi.org/10.3389/frph.2021.692249">Pascoal et al.</a> describe a rare form of endometriosis and highlight the importance of approaching this complex condition's diagnosis and treatment in a multidisciplinary approach.All authors provided critical feedback, helped shape the Editorial, reviewed, revised, and confirmed the final submitted version, and contributed equally. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Highlights in gynecology 2021/22

Endometriosis (EM) is characterized by the growth of endometrium-like tissue outside the uterus, leading to chronic inflammation and pelvic pain. Lesion proliferation, vascularization, and associated inflammation are the hallmark features of EM lesions. The legalization of recreational cannabinoids has garnered interest in the patient community and is contributing to a greater incidence of self medication; however, it remains unknown if cannabinoids possess marked disease-modifying properties. In this study, we assess the effects of synthetic cannabinoid, WIN 55212-2 (WIN 55), in EM-representative in vitro and in vivo syngeneic mouse models. WIN 55 reduced proliferation and angiogenesis in vitro, via MAPK/Akt-mediated apoptosis. These findings were corroborated in a mouse model of EM, where we found reduced TRPV1 expression in the dorsal root ganglia of the EM mouse model exposed to WIN 55, suggesting reduced signaling of pain stimuli. Ultimately, these pieces of evidence support the use of cannabinoid receptor agonists as a potential therapeutic intervention for EM associated pain and inflammation.

Endometriosis (EM) is characterized by the growth of endometrium-like tissue outside the uterus, leading to chronic inflammation and pelvic pain. Lesion proliferation, vascularization, and associated inflammation are the hallmark features of EM lesions. The legalization of recreational cannabinoids has garnered interest in the patient community and is contributing to a greater incidence of self medication; however, it remains unknown if cannabinoids possess marked disease-modifying properties. In this study, we assess the effects of synthetic cannabinoid, WIN 55212-2 (WIN 55), in EM-representative in vitro and in vivo syngeneic mouse models. WIN 55 reduced proliferation and angiogenesis in vitro, via MAPK/Akt-mediated apoptosis. These findings were corroborated in a mouse model of EM, where we found reduced TRPV1 expression in the dorsal root ganglia of the EM mouse model exposed to WIN 55, suggesting reduced signaling of pain stimuli. Ultimately, these pieces of evidence support the use of cannabinoid receptor agonists as a potential therapeutic intervention for EM associated pain and inflammation.

Synthetic Cannabinoid Agonist WIN 55212-2 Targets Proliferation, Angiogenesis, and Apoptosis via MAPK/AKT Signaling in Human Endometriotic Cell Lines and a Murine Model of Endometriosis

Extrapelvic endometriosis, although rare, can present in the musculoskeletal system of reproductive-age women and cause significant pain and morbidity. The pathophysiology of this disease is not well understood. In this study, we described the case of a 39-year-old women with an inner-thigh mass causing catamenial pain. Core-biopsy of the mass confirmed endometriosis and she was referred to minimally-invasive gynecology for management. Surgical excision was performed by a multidisciplinary team and she remains pain-free postoperatively on hormonal therapy. Unique to this case, the patient had a history of pelvic fracture. Through this case report, we discuss possible pathophysiologic mechanisms of extrapelvic musculoskeletal endometriosis including the stem/progenitor cell theory and the role that musculoskeletal trauma may have in the development of this condition. Gynecologists play an important role in the recognition, diagnosis, and management of musculoskeletal endometriosis.

Extrapelvic endometriosis, although rare, can present in the musculoskeletal system of reproductive-age women and cause significant pain and morbidity. The pathophysiology of this disease is not well understood. In this study, we described the case of a 39-year-old women with an inner-thigh mass causing catamenial pain. Core-biopsy of the mass confirmed endometriosis and she was referred to minimally-invasive gynecology for management. Surgical excision was performed by a multidisciplinary team and she remains pain-free postoperatively on hormonal therapy. Unique to this case, the patient had a history of pelvic fracture. Through this case report, we discuss possible pathophysiologic mechanisms of extrapelvic musculoskeletal endometriosis including the stem/progenitor cell theory and the role that musculoskeletal trauma may have in the development of this condition. Gynecologists play an important role in the recognition, diagnosis, and management of musculoskeletal endometriosis.

Case Report: Extrapelvic Endometriosis in the Medial Thigh

Background: An international collaborative study was conducted to determine the demographic and clinical profiles of Hispanic/Latinx endometriosis patients from Latin America and Spain using the Minimal Clinical Questionnaire developed by the World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect).Methods: This is a cross-sectional study to collect self-reported data on demographics, lifestyle, and endometriosis symptoms of Hispanic/Latinx endometriosis patients from April 2019 to February 2020. The EPHect Minimal Clinical Questionnaire (EPQ-M) was translated into Spanish. Comprehension and length of the translated survey were assessed by Spanish-speaking women. An electronic link was distributed via social media of endometriosis patient associations from 11 Latin American countries and Spain. Descriptive statistics (frequency, means and SD, percentages, and proportions) and correlations were conducted using SPSSv26.Results: The questionnaire was completed by 1,378 participants from 23 countries; 94.6% had self-reported diagnosis of endometriosis. Diagnostic delay was 6.6 years. Most participants had higher education, private health insurance, and were employed. The most common symptoms were back/leg pain (85.4%) and fatigue (80.7%). The mean number of children was 1.5; 34.4% had miscarriages; the mean length of infertility was 3.7 years; 47.2% reported pregnancy complications. The most common hormone treatment was oral contraceptives (47.0%). The most common comorbidities were migraines (24.1%), polycystic ovary syndrome (PCOS) (22.2%), and irritable bowel syndrome (21.1%). Most participants (97.0%) experienced pelvic pain during menses; for 78.7%, pain was severe; 86.4% reported dyspareunia. The mean age of dysmenorrhea onset was 16.2 years (SD ± 6.1). Hormone treatments were underutilized, while impact was substantial. Pain catastrophizing scores were significantly correlated with pain intensity (p < 0.001).Conclusion: This is the first comprehensive effort to generate a clinical–demographic profile of Hispanic/Latinx endometriosis patients. Differences in clinical presentation compared to other cohorts included higher prevalence and severity of dysmenorrhea and dyspareunia and high levels of pain catastrophizing. Though future studies are needed to dissect the impact of race and ethnicity on pain and impact, this profile is the first step to facilitate the recognition of risk factors and diagnostic features and promote improved clinical management of this patient population. The EPHect questionnaire is an efficient tool to capture data to allow comparisons across ethnicities and geographic regions and tackle disparities in endometriosis research.

Background: An international collaborative study was conducted to determine the demographic and clinical profiles of Hispanic/Latinx endometriosis patients from Latin America and Spain using the Minimal Clinical Questionnaire developed by the World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect).Methods: This is a cross-sectional study to collect self-reported data on demographics, lifestyle, and endometriosis symptoms of Hispanic/Latinx endometriosis patients from April 2019 to February 2020. The EPHect Minimal Clinical Questionnaire (EPQ-M) was translated into Spanish. Comprehension and length of the translated survey were assessed by Spanish-speaking women. An electronic link was distributed via social media of endometriosis patient associations from 11 Latin American countries and Spain. Descriptive statistics (frequency, means and SD, percentages, and proportions) and correlations were conducted using SPSSv26.Results: The questionnaire was completed by 1,378 participants from 23 countries; 94.6% had self-reported diagnosis of endometriosis. Diagnostic delay was 6.6 years. Most participants had higher education, private health insurance, and were employed. The most common symptoms were back/leg pain (85.4%) and fatigue (80.7%). The mean number of children was 1.5; 34.4% had miscarriages; the mean length of infertility was 3.7 years; 47.2% reported pregnancy complications. The most common hormone treatment was oral contraceptives (47.0%). The most common comorbidities were migraines (24.1%), polycystic ovary syndrome (PCOS) (22.2%), and irritable bowel syndrome (21.1%). Most participants (97.0%) experienced pelvic pain during menses; for 78.7%, pain was severe; 86.4% reported dyspareunia. The mean age of dysmenorrhea onset was 16.2 years (SD ± 6.1). Hormone treatments were underutilized, while impact was substantial. Pain catastrophizing scores were significantly correlated with pain intensity (p &lt; 0.001).Conclusion: This is the first comprehensive effort to generate a clinical–demographic profile of Hispanic/Latinx endometriosis patients. Differences in clinical presentation compared to other cohorts included higher prevalence and severity of dysmenorrhea and dyspareunia and high levels of pain catastrophizing. Though future studies are needed to dissect the impact of race and ethnicity on pain and impact, this profile is the first step to facilitate the recognition of risk factors and diagnostic features and promote improved clinical management of this patient population. The EPHect questionnaire is an efficient tool to capture data to allow comparisons across ethnicities and geographic regions and tackle disparities in endometriosis research.

Ibero-American Endometriosis Patient Phenome: Demographics, Obstetric-Gynecologic Traits, and Symptomatology

Introduction: High prevalence of gynecological conditions in women of Middle Eastern origin is reported, likely due to regional risk factors and mediators. The objective of this systematic review and meta-analysis is to investigate the prevalence of polycystic ovary syndrome (PCOS), endometriosis, uterine fibroids, and adenomyosis in women of Middle Eastern origin.Methods: MEDLINE, EMBASE, PsycINFO, Global Health, and Google Scholar databases were searched from database inception until 14 February 2021 to identify relevant studies. Peer-reviewed research articles that reported the prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern population were written in English or Arabic. The primary outcome was the estimated pooled prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern populations. The secondary outcome was to assess the evidence in the data for the presence of heterogeneity, by conducting subtype-pooled analysis of prevalence estimates of the conditions. Total weighted prevalence was calculated via Freeman–Tukey arcsine transformation and heterogeneity through the I2 statistic. Quality control was performed using GRADE criteria.Results: A total of 47 studies, 26 on PCOS, 12 on endometriosis, eight on uterine fibroids, and seven on adenomyosis, were included. The pooled prevalence of PCOS diagnosed according to the NIH criteria was 8.9% (95% CI: 6.5–11.7; prevalence range: 4.0–27.6%), with a higher prevalence from the Gulf Arab states (18.8%, 95% CI: 9.5–30.3; range: 12.1–27.6%). According to the Rotterdam criteria, the pooled prevalence of PCOS was 11.9% (95% CI: 7.1–17.7; range: 3.4–19.9%) with studies limited to the Persian and Levant regions. Endometriosis was diagnosed in 12.9% (95% CI: 4.2–25.4; range: 4.2–21.0%) of women undergoing laparoscopy, for any indication. Uterine fibroid and adenomyosis prevalence of women was 30.6% (95% CI: 24.9–36.7; range: 18.5–42.6%) and 30.8% (95% CI: 27.1–34.6, range: 25.6–37.7%), respectively. Heterogeneity was present between studies due to statistical and methodological inconsistencies between studies, and quality of evidence was low due to sample size and unrepresentative participant selection.Conclusion: This is the first review that has reported the prevalence of gynecological diseases in the Middle Eastern population, suggesting that gynecological morbidity is a public health concern. Due to the health disparities in women, further research is required to understand the relative roles of environmental and genetic factors in the region to serve as a benchmark for evaluation and comparative purposes with other populations.

Introduction: High prevalence of gynecological conditions in women of Middle Eastern origin is reported, likely due to regional risk factors and mediators. The objective of this systematic review and meta-analysis is to investigate the prevalence of polycystic ovary syndrome (PCOS), endometriosis, uterine fibroids, and adenomyosis in women of Middle Eastern origin.Methods: MEDLINE, EMBASE, PsycINFO, Global Health, and Google Scholar databases were searched from database inception until 14 February 2021 to identify relevant studies. Peer-reviewed research articles that reported the prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern population were written in English or Arabic. The primary outcome was the estimated pooled prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern populations. The secondary outcome was to assess the evidence in the data for the presence of heterogeneity, by conducting subtype-pooled analysis of prevalence estimates of the conditions. Total weighted prevalence was calculated via Freeman–Tukey arcsine transformation and heterogeneity through the I2 statistic. Quality control was performed using GRADE criteria.Results: A total of 47 studies, 26 on PCOS, 12 on endometriosis, eight on uterine fibroids, and seven on adenomyosis, were included. The pooled prevalence of PCOS diagnosed according to the NIH criteria was 8.9% (95% CI: 6.5–11.7; prevalence range: 4.0–27.6%), with a higher prevalence from the Gulf Arab states (18.8%, 95% CI: 9.5–30.3; range: 12.1–27.6%). According to the Rotterdam criteria, the pooled prevalence of PCOS was 11.9% (95% CI: 7.1–17.7; range: 3.4–19.9%) with studies limited to the Persian and Levant regions. Endometriosis was diagnosed in 12.9% (95% CI: 4.2–25.4; range: 4.2–21.0%) of women undergoing laparoscopy, for any indication. Uterine fibroid and adenomyosis prevalence of women was 30.6% (95% CI: 24.9–36.7; range: 18.5–42.6%) and 30.8% (95% CI: 27.1–34.6, range: 25.6–37.7%), respectively. Heterogeneity was present between studies due to statistical and methodological inconsistencies between studies, and quality of evidence was low due to sample size and unrepresentative participant selection.Conclusion: This is the first review that has reported the prevalence of gynecological diseases in the Middle Eastern population, suggesting that gynecological morbidity is a public health concern. Due to the health disparities in women, further research is required to understand the relative roles of environmental and genetic factors in the region to serve as a benchmark for evaluation and comparative purposes with other populations.