Endometriosis affects approximately 10% of women of reproductive age. Characteristics robustly associated with a greater risk for endometriosis include early age at menarche, short menstrual cycle length, and lean body size, whereas greater parity has been associated with a lower risk. Relationships with other potential characteristics including physical activity, dietary factors, and lactation have been less consistent, partially because of the need for rigorous data collection and a longitudinal study design. Critical methodologic complexities include the need for a clear case definition; valid selection of comparison/control groups; and consideration of diagnostic bias and reverse causation when exploring demographic characteristics, medical history, and lifestyle factors. Reviewers and editors must demand a detailed description of rigorous methods to facilitate comparison and replication to advance our understanding of endometriosis.

Increasing evidence suggests that endometriosis patients are at higher risk of several chronic diseases. Although the underlying mechanisms are not yet understood, the available data to date suggest that endometriosis is not harmless with respects to women's long-term health. If these relationships are confirmed, these findings may have important implications in screening practices and in the management and care of endometriosis patients.

This work was supported by the National Institutes of Health (grant numbers: UM1 CA176726, HD52473, HD57210, T32DK007703, T32HD060454, K01DK103720). We have no competing interests to declare.

BACKGROUND Endometriosis is an often chronic, inflammatory gynaecologic condition affecting 190 million women worldwide. Studies have reported an elevated cancer risk among patients with endometriosis. However, prior research has included methodologic issues that impede valid and robust interpretation. OBJECTIVE AND RATIONALE We conducted a meta-analysis of studies investigating the association between endometriosis and cancer risk and analysed the results by methodologic characteristics. We discuss the implications of cancer screening in patients and management challenges faced by clinicians. SEARCH METHODS We searched PubMed and Embase databases for eligible studies from inception through 24 October 2019. We included cohort and case-control studies examining the association between endometriosis and cancer risk; cross-sectional studies and case reports were excluded. Publications had to present risk/rate/odds estimates with 95% CI. Random effects meta-analysis was used to estimate summary relative risks (SRR) and CIs. Heterogeneity across studies was assessed by the Q test and I2 statistics, and publication bias using Egger's and Begg's tests. Risk of bias and quality of the included studies were assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool. OUTCOMES Forty-nine population-based case-control and cohort studies were included. Twenty-six studies were scored as having a ‘serious’/‘critical’ risk of bias, and the remaining 23 ‘low’/‘moderate’. Cancer-specific analyses showed a positive association between endometriosis and ovarian cancer risk (SRR = 1.93, 95% CI = 1.68–2.22; n = 24 studies) that was strongest for clear cell (SRR = 3.44, 95% CI = 2.82–4.42; n = 5 studies) and endometrioid (SRR = 2.33, 95% CI = 1.82–2.98; n = 5 studies) histotypes (Pheterogeneity < 0.0001), although with significant evidence of both heterogeneity across studies and publication bias (Egger’s and Begg’s P-values < 0.01). A robust association was observed between endometriosis and thyroid cancer (SRR = 1.39, 95% CI =1.24–1.57; n = 5 studies), a very small association with breast cancer (SRR = 1.04, 95% CI =1.00–1.09; n = 20 studies) and no association with colorectal cancer (SRR = 1.00, 95% CI =0.87–1.16; n = 5 studies). The association with endometrial cancer was not statistically significant (SRR = 1.23, 95% CI =0.97–1.57; n = 17 studies) overall and wholly null when restricted to prospective cohort studies (SRR = 0.99, 95% CI =0.72–1.37; n = 5 studies). The association with cutaneous melanoma was also non-significant (SRR = 1.17, 95% CI =0.97–1.41; n = 7 studies) but increased in magnitude and was statistically significant when restricted to studies with low/moderate risk of bias (SRR = 1.71, 95% CI = 1.24–2.36, n = 2 studies). The most robust finding both in terms of statistical significance and magnitude of effect was an inverse association with cervical cancer (SRR = 0.68, 95% CI =0.56–0.82; n = 4 studies); however, this result has a high potential to reflect heightened access to detection of dysplasia for women who reached an endometriosis diagnosis and is thus likely not causal. Several additional cancer types were explored based on <4 studies. WIDER IMPLICATIONS Endometriosis was associated with a higher risk of ovarian and thyroid, and minimally (only 4% greater risk) with breast cancer, and with a lower risk of cervical cancer. However, this meta-analysis confirms that: a majority of studies had severe/critical risk of bias; there is impactful heterogeneity across studies—and for ovarian cancer, publication bias; and causal inference requires temporality, which in many studies was not considered. We discuss the implications of these potential associations from the perspectives of patients with endometriosis, clinicians involved in their care, and scientists investigating their long-term health risks.

RR, relative risk; ref, reference; GDM, gestational diabetes mellitus. Data are n/N (%) unless otherwise specified. * 95% confidence interval. † 99% confidence interval. ‡ Among pregnancies. § Multivariable model adjusted for age, year of pregnancy, and year of pregnancy interaction term. ║ Multivariable model additionally adjusted for race, age at menarche, menstrual cycle length between ages 18 and 22 years, BMI at age 18 years, smoking status, alcohol intake, parity, history of infertility, multiple gestation (preeclampsia or gestational hypertension, preterm birth) and preterm birth (low birth weight). ¶ Among births.

Clinical presentation, outcomes, and duration of COVID-19 has ranged dramatically. While some individuals recover quickly, others suffer from persistent symptoms, collectively known as long COVID, or post-acute sequelae of SARS-CoV-2 (PASC). Most PASC research has focused on hospitalized COVID-19 patients with moderate to severe disease. We used data from a diverse population-based cohort of Arizonans to estimate prevalence of PASC, defined as experiencing at least one symptom 30 days or longer, and prevalence of individual symptoms. There were 303 non-hospitalized individuals with a positive lab-confirmed COVID-19 test who were followed for a median of 61 days (range 30–250). COVID-19 positive participants were mostly female (70%), non-Hispanic white (68%), and on average 44 years old. Prevalence of PASC at 30 days post-infection was 68.7% (95% confidence interval: 63.4, 73.9). The most common symptoms were fatigue (37.5%), shortness-of-breath (37.5%), brain fog (30.8%), and stress/anxiety (30.8%). The median number of symptoms was 3 (range 1–20). Amongst 157 participants with longer follow-up (≥60 days), PASC prevalence was 77.1%.

The work for this paper was supported by the following: S.M.: Reproductive Scientist Development Program HD000849, and the Building Interdisciplinary Research Careers in Women's Health HD043444, the Boston University CTSI 1UL1TR001430, and a research grant from the Boston University Department of Obstetrics and Gynecology, S.A.M.: R01HD57210 from the National Institute of Child Health and Human Development and the Massachusetts Institute of Technology Center for Environmental Health Sciences Translational Pilot Project Program, R01CA50385 from the National Cancer Institute, J.E.H. and F.L.: 5R01ES017017 from the National Institute for Environmental Health Sciences, 5 P42 ES007381 from the National Institute of Environmental Health at the National Institute of Health. L.V.F.: T32HD060454 in reproductive, perinatal, and pediatric epidemiology from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Nurses' Health Study II is additionally supported by infrastructure grant UM1CA176726 from the National Cancer Institute, NIH, U.S. Department of Health and Human Services. The authors have no actual or potential competing financial interests to disclose.

BACKGROUND Endometriosis is a chronic, burdensome condition that is historically understudied. Consequently, there is a lack of understanding of the etiology of the disease and its associated symptoms, including infertility and chronic pelvic pain (CPP). Endometriosis development is influenced by estrogen metabolism and inflammation, which are modulated by several factors including the microbiome and the estrobolome (the collection of genes encoding estrogen-metabolizing enzymes in the gut microbiome). Therefore, there is increasing interest in understanding the role of microbiota in endometriosis etiology. OBJECTIVE AND RATIONALE To date, there is no cure for endometriosis and treatment options often are ineffective. This manuscript will review the potential relationship between the microbiome and endometriosis, infertility and CPP and highlight the available data on the microbiome in relation to endometriosis and its related symptoms. The overarching goal of this manuscript is to inform future microbiome research that will lead to a deeper understanding of the etiology of the disease and possible diagnostic modalities and treatments. The potential impact of the microbiome on estrogen regulation modulated by the estrobolome, as well as inflammation and other endometriosis-promoting mechanisms within the genital tract, will be reviewed. The methodological limitations of microbiome-related studies will be critically assessed to provide improved guidelines for future microbiome and clinical studies. SEARCH METHODS PubMed databases were searched using the following keywords: endometriosis AND microbiome, infertility AND microbiome, pelvic pain AND microbiome, IVF (in-vitro fertilization) AND microbiome, endometriosis AND infertility. Clinical and preclinical animal trials that were eligible for review, and related to microbiome and endometriosis, infertility or CPP were included. All available manuscripts were published in 2002–2021. OUTCOMES In total, 28 clinical and 6 animal studies were included in the review. In both human and animal studies, bacteria were enriched in endometriosis groups, although there was no clear consensus on specific microbiota compositions that were associated with endometriosis, and no studies included infertility or CPP with endometriosis. However, bacterial vaginosis-associated bacteria and Lactobacillus depletion in the cervicovaginal microbiome were associated with endometriosis and infertility in the majority (23/28) of studies. Interpretation of endometrial studies is limited owing to a variety of methodological factors, discussed in this review. In addition, metadata outlining antibiotic usage, age, race/ethnicity, menopausal status and timing of sample collection in relation to diagnosis of endometriosis was not consistently reported. Animal studies (6/6) support a bidirectional relationship between the gut microbiota and endometriosis onset and progression. WIDER IMPLICATIONS There is evidence that a dysbiotic gut or genital microbiota is associated with multiple gynecologic conditions, with mounting data supporting an association between the microbiome and endometriosis and infertility. These microbiomes likely play a role in the gut-brain axis, which further supports a putative association with the spectrum of symptoms associated with endometriosis, including infertility and CPP. Collectively, this review highlights the demand for more rigorous and transparent methodology and controls, consistency across the field, and inclusion of key demographic and clinical characteristics of disease and comparison participants. Rigorous study designs will allow for a better understanding of the potential role of the microbiome in endometriosis etiology and the relationship to other disorders of the female reproductive tract.