Investigational drugs for the treatment of dysmenorrhea.

INTRODUCTION: Dysmenorrhea is the most common cause of gynecological pain among women that has considerable impact on quality of life and psychosocial wellbeing. Non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal therapies are most commonly used to treat dysmenorrhea. However, given these drugs are often associated with bothersome side effects and are less effective when there is an underlying cause contributing to dysmenorrhea (e.g. endometriosis), a patient-centered approach to managing dysmenorrhea is important. Various new drugs are currently being investigated for the treatment of primary and secondary dysmenorrhea. AREAS COVERED: This review provides an updated overview on new therapeutic targets and investigational drugs for the treatment of primary and secondary dysmenorrhea. The authors describe the clinical development and implications of these drugs. EXPERT OPINION: Among the investigative drugs discussed in this review, anti-inflammatories show the most promising results for the treatment of dysmenorrhea. However, given some trials have considerable methodological limitations, many drugs cannot be currently recommended. Research focused on understanding the mechanisms involved in menstruation and its associated symptoms will be important to identify new therapeutic targets for dysmenorrhea. Further robust clinical trials are required to better understand the efficacy and safety of investigational drugs for treating primary and secondary dysmenorrhea.

Distribution of smooth muscle actin and collagen in superficial peritoneal endometriotic lesions varies from the surrounding microenvironment.

RESEARCH QUESTION: Do different subtypes of superficial peritoneal endometriotic lesions exist, based on the presence and morphology of smooth muscle, collagen fibres and immune cell populations? DESIGN: A retrospective cohort study of 24 patients, from across the menstrual cycle, with surgically and histologically confirmed endometriosis. Immunofluorescence was used to delineate the CD10 stromal area of lesions (n = 271 lesions from 67 endometriotic biopsies), and then smooth muscle actin (SMA) positive tissue and immune cell populations (CD45+ and CD68+) were quantified within and adjacent to these lesions. Second harmonic generation microscopy was used to evaluate the presence and morphology of type-1 collagen fibres within and surrounding lesions. RESULTS: Overall, immune cell numbers and the area of SMA and collagen within endometriotic lesions tended to be low, but a spectrum of presentations significantly varied, particularly in the adjacent tissue microenvironment, based on lesion locations, the morphology of endometriotic gland profiles, or both. Lesions in which collagen fibres formed well aligned capsules around the CD10+ stromal border were identified compared with lesions in which collagen fibre distribution was random. Considerable inter- and intra-patient variability in the morphology of SMA and collagen was observed within and surrounding lesions. CONCLUSION: These data demonstrate considerable diversity in the presence of immune cells and morphology of SMA and collagen within, but even more so, surrounding endometriotic lesions, even within individual patients. This heterogeneity, especially within individual patients, presents a challenge to incorporating these cell and tissue types into any new endometriosis classification systems or prognostic approaches.

Sexual and reproductive health knowledges: a study with Pacific young people enrolled in an Aotearoa New Zealand tertiary institution.

Pacific young people living in Aotearoa New Zealand experience disparities in their sexual and reproductive health outcomes, thought to stem from cultural differences and educational inequities. Although these barriers have been characterised in literature, their influence on Pacific youth's understandings of sexual and reproductive health have been relatively unexplored. This study investigated the sexual and reproductive health knowledge of Pacific students enrolled at a university in Aotearoa New Zealand in 2020 and where they gained this knowledge. The study used the theoretical framework of the (revitalised) Fonofale health model and was guided by the Kakala research methodology. Data were collected by means of an online survey comprised of open-ended questions and Likert scales, completed by eighty-one eligible students. Open-ended questions were analysed for general themes and responses to Likert scale items are reported using descriptive statistical analysis. The study found that Pacific youth have strong foundations of health knowledge that is heavily influenced by Polynesian cultural beliefs. Both formal and non-formal learning environments were important in developing participants' health knowledge of these topics and for encouraging independent help-seeking behaviours. This is the first reported study to investigate the sexual and reproductive health knowledges of a pan-Pacific tertiary cohort of young people.

Extensive heterogeneity in the expression of steroid receptors in superficial peritoneal endometriotic lesions.

RESEARCH QUESTION: Is the expression of steroid hormone receptors (oestrogen receptor-α and progesterone receptor A/B) and proliferative markers (Bcl-2 and Ki67) uniform among superficial peritoneal endometriotic lesions? DESIGN: A retrospective cohort study of 24 patients with surgically and histologically confirmed endometriosis. Immunofluorescence was used to determine the proportion of oestrogen receptor-α (ERα), progesterone receptor A/B, Bcl-2 and Ki67 positive cells in 271 endometriotic lesions (defined as endometriotic gland profile/s within an individual region of CD10 stromal immunostaining from a single biopsy) from 67 endometriotic biopsies from 24 patients. Data were analysed to examine associations related to menstrual cycle stage, lesion location and gland morphology. RESULTS: Oestrogen receptor-α and progesterone receptor A/B expression in superficial peritoneal endometriotic lesions was extremely heterogeneous. Bcl-2 immunostaining in endometriotic lesions was also variable, whereas Ki67 immunostaining was minimal. Menstrual cycle stage associations were limited in steroid hormone receptor and Bcl-2 expression in lesions. Patterns in progesterone receptor A/B and Bcl-2 immunostaining were associated with lesion location. Bcl-2 was differentially expressed, based on lesion gland morphology. CONCLUSIONS: These data demonstrate considerable diversity in the expression of steroid hormone receptors and Bcl-2 between lesions, even within an individual patient.

Fertility and infertility uses of menstrual apps from the perspectives of healthcare providers and patients.

BACKGROUND: Menstrual cycle tracking apps are increasingly used by those trying to conceive as well as those diagnosed and treated for infertility. However, the small amount of existing research about the use of these apps does not include the perspectives of healthcare providers. AIMS: This study explores how healthcare providers describe the role of menstrual apps in fertility and infertility health care, and how this compares with patients' views. MATERIALS AND METHODS: Responses were collected from an online survey (n = 37 providers and n = 89 patients) and online focus groups (n = 4 providers and n = 6 patients) and analysed using reflexive thematic analysis. RESULTS: Healthcare providers, as well as some patients, expressed doubts about the accuracy of app estimates of the timing of ovulation. By contrast, many patients, but no healthcare providers, were enthusiastic about ovulation estimates provided by their apps. Apps were described by both groups as having a role in diagnosing and treating infertility, with healthcare providers emphasising the calendar history function of the apps supporting treatment, and patients focused on recognising and diagnosing infertility. CONCLUSIONS: This exploratory study suggests that apps are viewed by both healthcare providers and patients as having a potential role in fertility and infertility healthcare. Although patients and app users are attentive to app estimates of ovulation timing, healthcare providers are sceptical.

Retrospective review of endometriosis surgery at Te Whatu Ora - Capital and Coast.

INTRODUCTION: Endometriosis is an under-researched disease, with Aotearoa-specific data severely lacking. Current estimates of parameters such as rates of endometriosis diagnosis, indication for surgery and sites of disease are based on international data. There is currently no published data on endometriosis surgeries in Aotearoa New Zealand. AIMS: We aimed to describe the laparoscopic surgeries conducted for suspected endometriosis at Te Whatu Ora - Capital and Coast, including the prevalence of endometriosis in this cohort, indication for surgery, symptoms experienced, endometriosis stage and sites involved, number of repeat laparoscopies, and prevalence of endometriosis at repeat surgery. MATERIALS AND METHODS: To conduct this retrospective cross-sectional study, data were extracted from Te Whatu Ora - Capital and Coast systems to identify all records indicating surgery for suspected endometriosis during 2018 and 2019. Variables investigated included age, ethnicity, endometriosis diagnosis (International Classification of Diseases-10 Clinical Modification coding), stage of endometriosis, histological report and endometriosis symptoms (pain and/or fertility). RESULTS: There were 436 surgeries for suspected endometriosis performed during 2018 and 2019, and endometriosis was diagnosed in 68.3% of these surgeries. Pacific and Asian people were under-represented in the study cohort compared to the demographics of the hospital catchment area (Pacific: 3.0% vs 8.4%, Asian: 9.9% vs 12.9%). The most common indication for surgery was pain. There were 76 surgeries performed for suspected recurrence of endometriosis, and endometriosis was identified in 55.6% of these. CONCLUSIONS: Endometriosis surgeries in this hospital in Aotearoa show similar presentations and surgical findings to international data. Our findings highlight areas requiring more research in an Aotearoa-specific context.

Androgen signalling in the ovaries and endometrium.

Currently, our understanding of hormonal regulation within the female reproductive system is largely based on our knowledge of estrogen and progesterone signalling. However, while the important functions of androgens in male physiology are well known, it is also recognized that androgens play critical roles in the female reproductive system. Further, androgen signalling is altered in a variety of gynaecological conditions, including endometriosis and polycystic ovary syndrome, indicative of regulatory roles in endometrial and ovarian function. Co-regulatory mechanisms exist between different androgens, estrogens, and progesterone, resulting in a complex network of steroid hormone interactions. Evidence from animal knockout studies, in vitro experiments, and human data indicate that androgen receptor expression is cell-specific and menstrual cycle stage-dependent, with important regulatory roles in the menstrual cycle, endometrial biology, and follicular development in the ovaries. This review will discuss the expression and co-regulatory interactions of androgen receptors, highlighting the complexity of the androgen signalling pathway in the endometrium and ovaries, and the synthesis of androgens from additional alternative pathways previously disregarded as male-specific. Moreover, it will illustrate the challenges faced when studying androgens in female biology, and the need for a more in-depth, integrative view of androgen metabolism and signalling in the female reproductive system.

Cyclic processes in the uterine tubes, endometrium, myometrium, and cervix: pathways and perturbations.

This review leads the 2023 Call for Papers in MHR: 'Cyclical function of the female reproductive tract' and will outline the complex and fascinating changes that take place in the reproductive tract during the menstrual cycle. We will also explore associated reproductive tract abnormalities that impact or are impacted by the menstrual cycle. Between menarche and menopause, women and people who menstruate living in high-income countries can expect to experience ∼450 menstrual cycles. The primary function of the menstrual cycle is to prepare the reproductive system for pregnancy in the event of fertilization. In the absence of pregnancy, ovarian hormone levels fall, triggering the end of the menstrual cycle and onset of menstruation. We have chosen to exclude the ovaries and focus on the other structures that make up the reproductive tract: uterine tubes, endometrium, myometrium, and cervix, which also functionally change in response to fluctuations in ovarian hormone production across the menstrual cycle. This inaugural paper for the 2023 MHR special collection will discuss our current understanding of the normal physiological processes involved in uterine cyclicity (limited specifically to the uterine tubes, endometrium, myometrium, and cervix) in humans, and other mammals where relevant. We will emphasize where knowledge gaps exist and highlight the impact that reproductive tract and uterine cycle perturbations have on health and fertility.

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

The role of menstrual apps in healthcare: provider and patient perspectives.

AIM: This study aimed to understand the role that menstrual apps ("period tracking apps" or "fertility apps") could perform in healthcare. METHODS: Expert stakeholders including healthcare providers, app users, and patients offered perspectives on potential benefits, concerns, and role of apps in healthcare. Responses from an online qualitative survey (N=144) and three online focus groups (N=10) were analysed using reflexive thematic analysis. RESULTS: The role of menstrual apps in healthcare could include keeping a record of cycle dates and symptoms and assisting in the management of menstrual disorders, diseases and conditions linked to the menstrual cycle such as endometriosis, PCOS, infertility, and perimenopause. Respondents are using app calendars and symptom tracking to improve communication between healthcare providers and patients, while also expressing concerns about inaccuracies and other uses of data. Respondents wished for assistance in managing their health, while noting that apps currently are limited and suggesting that apps need to be better suited to Aotearoa New Zealand specific menstrual disorders, diseases and life stages. CONCLUSIONS: Menstrual apps may have a role in healthcare, but further research needs to develop and evaluate app functions and accuracy as well as providing education and guidelines for whether and when apps are appropriate for healthcare.

Unmet Needs in Endometriosis: Lessons from COVID-19.

Background: One key challenge of the COVID-19 pandemic is health care access. Government-imposed restrictions and increased health care burden have induced considerable changes to health care services and their delivery. These are likely to have substantially impacted those with chronic conditions such as endometriosis, as they require sustained management. Aims: Our objective was to explore the impact of the COVID-19 pandemic on the experience of people with endometriosis, and to use this information to inform health care delivery for the management of chronic conditions in a COVID-normal future. Materials and Methods: Invitation to participate in an open-ended online survey through social media of Australian endometriosis organizations and the Royal Women's Hospital, Melbourne. Surveys were analyzed qualitatively through template analysis. Results: Of 576 surveys returned, 329 reported COVID-19 having an impact. Fifteen areas of impact were identified and grouped under three domains: impact on access to health care services, impact on daily life, and impact of isolation. Common impacts included reduced access to health care services, improved symptom management due to decreased day-to-day travel and work-from-home arrangements, and both positive and negative views of telehealth services. Conclusions: This study provides in-depth insight into the experiences of people with endometriosis during the COVID-19 pandemic, confirming previous studies' findings and offering insight into discrepancies between the Australian Healthcare system categorization of surgeries as "non-essential," and patient views of these procedures as "essential" to their well-being. Results may inform future adjustments to health care services and delivery to improve the lives of people with endometriosis, and by extension, other chronic conditions.

Lessons from implementing the Australian National Action Plan for Endometriosis.

Abstract: Endometriosis is a common yet under-recognised chronic disease with one in nine (more than 830,000) women and those assigned female at birth diagnosed with endometriosis by the age of 44 years in Australia. In 2018, Australia was the first country to develop a roadmap and blueprint to tackle endometriosis in a nationwide, coordinated manner. This blueprint is outlined in the National Action Plan for Endometriosis (NAPE), created from a partnership between government, endometriosis experts and advocacy groups. The NAPE aims to improve patient outcomes in the areas of awareness and education, clinical management and care and research. As researchers and clinicians are working to improve the lives of those with endometriosis, we discuss our experiences since the launch of the plan to highlight areas of consideration by other countries when developing research priorities and clinical plans. Historically, major barriers for those with endometriosis have been twofold; first, obtaining a diagnosis and secondly, effective symptom management post-diagnosis. In recent years, there have been calls to move away from the historically accepted 'gold-standard' surgical diagnosis and single-provider specialist care. As there are currently no reliable biomarkers for endometriosis diagnosis, specialist endometriosis scans and MRI incorporating artificial intelligence offer a novel method of visualisation and promising affordable non-invasive diagnostic tool incorporating well-established technologies. The recognised challenges of ongoing pain and symptom management, a holistic interdisciplinary care approach and access to a chronic disease management plan, could lead to improved patient outcomes while reducing healthcare costs. Lay summary: Endometriosis is a chronic disease where tissue like the lining of the uterus is found in other locations around the body. For the 830,000 people living with endometriosis in Australia, this often results in an immense burden on all aspects of daily life. In 2018, Australia was the first country to introduce a roadmap and blueprint to tackle endometriosis in a nationwide coordinated manner with the National Action Plan for Endometriosis. This plan was created as a partnership between government, endometriosis experts and advocacy groups. There are several other countries who are now considering similar plans to address the burden of endometriosis. As researchers and clinicians are working to improve the lives of those with endometriosis, we share our experiences and discuss areas that should be considered when developing these national plans, including diagnostic pathways without the need for surgery, and building new centres of expertise in Endometriosis and Pelvic Pain.

Is there a role for small molecule metabolite biomarkers in the development of a diagnostic test for endometriosis?

Endometriosis is a disease defined by the presence of benign lesions of endometrial-like glands and stroma outside the endometrial cavity. Affecting an estimated 11.4% of Australian women, symptoms include chronic pelvic pain, dysmenorrhea and infertility. The current gold standard of diagnosis requires an expensive and invasive laparoscopic surgery, resulting in delayed time to treatment. The identification of a non-invasive endometriosis biomarker - a measurable factor correlating with disease presence or activity - has therefore become a priority in endometriosis research, although no biomarker has yet been validated. As small molecule metabolites and lipids have emerged as a potential focus, this review with systematic approach, aims to summarize studies examining metabolomic biomarkers of endometriosis in order to guide future research. EMBASE, PubMed and Web of Science were searched using keywords: lipidomics OR metabolomics OR metabolome AND diagnostic tests OR biomarkers AND endometriosis, and only studies written in English from August 2000 to August 2020 were included. Twenty-nine studies met inclusion and exclusion criteria and were included. These studies identified potential biomarkers in serum, ectopic tissue, eutopic endometrium, peritoneal fluid, follicular fluid, urine, cervical swabs and endometrial fluid. Glycerophospholipids were identified as potential biomarkers in all specimens, except urine and cervical swab specimens. However, no individual molecule or metabolite combination has reached clinical diagnostic utility. Further research using large study populations with robust patient phenotype and specimen characterisation is required if we are to make progress in identifying and validating a non-invasive diagnostic test for endometriosis.

An Aotearoa New Zealand survey of the impact and diagnostic delay for endometriosis and chronic pelvic pain.

Chronic pelvic pain (CPP) causes important negative effects on quality of life. Endometriosis is the most common cause of CPP in females, and diagnostic delay is over six years internationally. Data remain scarce for CPP impact or diagnostic delay in Aotearoa New Zealand. This study used an online survey to explore the impact of CPP on various life domains for those aged over 18. Additionally, for those with an endometriosis diagnosis, diagnostic delay and factors affecting this over time were explored. There were 800 respondent (620 with self-reported endometriosis). CPP symptoms, irrespective of final diagnosis, started prior to age 20 and negatively impacted multiple life domains including employment, education, and relationships. Mean diagnostic delay for those with endometriosis was 8.7 years, including 2.9 years between symptom onset and first presentation and 5.8 years between first presentation and diagnosis. Five doctors on average were seen prior to diagnosis. However, there was a reduction in the interval between first presentation and diagnosis over time, from 8.4 years for those presenting before 2005, to two years for those presenting after 2012. While diagnostic delay is decreasing, CPP, irrespective of aetiology, continues to have a significant negative impact on the lives of those affected.

Fetal resorption coincides with dysregulated LH secretion in AMH-overexpressing mice.

Female anti-Müllerian hormone (AMH) overexpressing (Thy1.2-AMHTg/0) mice experience fetal resorption (miscarriage) by mid-gestation. This study examined whether the ovary, uterine implantation sites and hypothalamus are potential sites of AMH action, as AMH type-2 receptor (AMHR2) expression is reported in each tissue. Pregnancy in Thy1.2-AMHTg/0 mice was compared to wild-type (WT) mice via histological examination of implantation sites, hormone assays, embryo culture and embryo transfer. Uterine AMH and AMHR2 expression was examined by RT-qPCR and immunohistochemistry. The first signs of fetal resorption in the Thy1.2-AMHTg/0 dams occurred at embryonic day 9.5 (E9.5) with 100% of fetuses resorbing by E13.5. Cultured embryos from Thy1.2-AMHTg/0 dams had largely normal developmental rates but a small proportion experienced a minor developmental delay relative to embryos from WT dams. However, embryos transferred from WT donor females always failed to survive to term when transferred into Thy1.2-AMHTg/0 dams. Amh and Amhr2 mRNA was detected in the gravid uterus but at very low levels relative to expression in the ovaries. Progesterone and estradiol levels were not significantly different between WT and Thy1.2-AMHTg/0 dams during pregnancy but luteinizing hormone (LH) levels were significantly elevated in Thy1.2-AMHTg/0 dams at E9.5 and E13.5 relative to WT dams. Collectively, these experiments suggest that AMH overexpression does not cause fetal resorption through an effect on oocytes or preimplantation embryo development. The Thy1.2-AMHTg/0 fetal resorption phenotype is nearly identical to that of transgenic LH overexpression models, suggesting that neuroendocrine mechanisms may be involved in the cause of the miscarriage.

Correction: Dilated Thin-Walled Blood and Lymphatic Vessels in Human Endometrium: A Potential Role for VEGF-D in Progestin-Induced Break-Through Bleeding.

[This corrects the article DOI: 10.1371/journal.pone.0030916.].

Comparing endometriotic lesions with eutopic endometrium: time to shift focus?

Endometriosis is a heterogeneous disease in terms of patient symptoms, treatment responsiveness and the presentation of endometriotic lesions. This article explores the histological features of endometriotic lesions, highlighting their sometimes underappreciated heterogeneity. We note the variability in evidence for and against the menstrual cycle responsiveness of lesions and consider the utility of drawing parallels between endometriotic lesions and eutopic endometrium. We ask whether histopathologic features beyond just the presence/absence of endometrial-like glands and/or stroma could help improve disease stratification. At the same time, we acknowledge the desire of many clinicians and patients to avoid invasive surgery thereby limiting the ability to histologically phenotype lesions. The ability to derive clinically useful histological information from endometriotic lesions, in association with patient data, would be invaluable to clinicians to help improve treatment options in such a diverse group of patients. However, in suggesting that a shift in focus may enable the development of a better patient stratification system, we recognise that our wish for a single comprehensive stratification system may be beyond reach for a disease of such diverse presentation.

Elucidating the role of long intergenic non-coding RNA 339 in human endometrium and endometriosis.

Endometriosis is a complex disease, influenced by genetic factors. Genetic markers associated with endometriosis exist at chromosome 1p36.12 and lead to altered expression of the long intergenic non-coding RNA 339 (LINC00339), however, the role of LINC00339 in endometriosis pathophysiology remains unknown. The aim of this work was to characterize the expression patterns of LINC00339 mRNA in endometrium and endometriotic lesions in situ and to determine the functional role of LINC00339 in human endometrium. We employed RNA-sequencing (RNA-seq), quantitative RT-PCR and in situ hybridization to investigate the abundance of LINC00339 transcripts in endometrium and endometrial cell lines and to describe the pattern and localization of LINC00339 expression in endometrium and endometriotic lesions. LINC00339 mRNA expression was manipulated (overexpressed and silenced) in endometrial stromal cell lines and RNA-seq data from overexpression models were analysed using online bioinformatics platforms (STRING and Ingenuity Pathway Analysis) to determine functional processes. We demonstrated the expression of LINC00339 in endometriotic lesions for the first time; we found LINC00339 expression was restricted to the lesion foci and absent in surrounding non-lesion tissue. Furthermore, manipulation of LINC00339 expression in endometrial stromal cell lines significantly impacted the expression of genes involved in immune defence pathways. These studies identify a novel mechanism for LINC00339 activity in endometrium and endometriosis, paving the way for future work, which is essential for understanding the pathogenesis of endometriosis.

Illicit Cannabis Usage as a Management Strategy in New Zealand Women with Endometriosis: An Online Survey.

Background: Endometriosis affects around 10% of women worldwide. Many women with endometriosis struggle with finding adequate pain management, and data from other countries suggest that women use cannabis, either legal or illicit, to help manage their endometriosis symptoms. The aim of this study was to determine use of cannabis where endometriosis was self-identified as a condition that was being treated with cannabis, as well as the impact of cannabis use on the usage on other pharmaceuticals. Materials and Methods: A cross-sectional online survey of those using cannabis for health-related conditions run between May and July 2019. This article reports on the subset of this larger data set for those reporting they had a diagnosis of endometriosis and/or polycystic ovary syndrome. Data were collected on demographics, modes of cannabis administration, symptoms treated, changes in pharmaceutical usage, and adverse events. Results: Two hundred thirteen valid responses were analyzed. Mean age of respondents was 32 years and 79.8% were current cannabis users. The most common outcomes that cannabis was used for were to improve pain relief (95.5%) and to improve sleep (95.5%). Respondents reported that their symptom was "much better" for pain (81%), sleep (79%), and nausea or vomiting (61%). Over three-quarters (81.4%) indicated cannabis had reduced their normal medication usage. Over half (59%) were able to completely stop a medication, most commonly (66%) analgesics. Opioids (40%) were the most common class of analgesic stopped. Conclusions: Cannabis is reported as an effective intervention for pain and other endometriosis symptoms with potential substitution effects on opioid usage.