Despite an estimated prevalence of 10% in women, the etiology of endometriosis remains poorly understood. Over recent decades, endometriosis has been associated with risk of several chronic diseases, such as cancer, autoimmune diseases, asthma/atopic diseases and cardiovascular diseases. A deeper understanding of these associations is needed as they may provide new leads into the causes or consequences of endometriosis. This review summarizes the available epidemiological findings on the associations between endometriosis and other chronic diseases and discusses hypotheses for underlying mechanisms, potential sources of bias and methodological complexities. We performed a comprehensive search of the PubMed/Medline and ISI Web of Knowledge databases for all studies reporting on the associations between endometriosis and other diseases published in English through to May 2014, using numerous search terms. We additionally examined the reference lists of all identified papers to capture any additional articles that were not identified through computer searches. We identified 21 studies on the associations between endometriosis and ovarian cancer, 14 for breast cancer, 8 for endometrial cancer, 4 for cervical cancer, 12 for cutaneous melanoma and 3 for non-Hodgkin's lymphoma, as well as 9 on the links between endometriosis and autoimmune diseases, 6 on the links with asthma and atopic diseases, and 4 on the links with cardiovascular diseases. Endometriosis patients were reported to be at higher risk of ovarian and breast cancers, cutaneous melanoma, asthma, and some autoimmune, cardiovascular and atopic diseases, and at decreased risk of cervical cancer. 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.

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. 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. 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. 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. 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.

Is there a temporal relationship between endometriosis and infertility? Endometriosis is associated with a higher risk of subsequent infertility, but only among women age <35 years. Endometriosis is the most commonly observed gynecologic pathology among infertile women undergoing laparoscopic examination. Whether endometriosis is a cause of infertility or an incidental discovery during the infertility examination is unknown. This study included data collected from 58 427 married premenopausal female nurses 12 months) among women with and without endometriosis. We identified 4612 incident cases of infertility due to any cause over 362 219 person-years of follow-up. Compared with women without a history of endometriosis, women with endometriosis had an age-adjusted 2-fold increased risk of incident infertility (HR = 2.12, 95% CI = 1.76–2.56) that attenuated slightly after accounting for parity. The relationship with endometriosis was only observed among women <35 years of age (multivariate HR 50 000 women accurately classified as endometriosis-free, minimizing the impact of exposure misclassification on the effect estimates. This study supports a temporal association between endometriosis and infertility risk. Our prospective analysis indicates a possible detection bias in previous studies, with our findings suggesting that the infertility risk posed by endometriosis is about half the estimates observed in cross-sectional analyses. 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.

Can a counseling tool be developed for women desiring elective oocyte cryopreservation to predict the likelihood of live birth based on age and number of oocytes frozen? Using data from ICSI cycles of a population of women with uncompromised ovarian reserve, an evidence-based counseling tool was created to guide women and their physicians regarding the number of oocytes needed to freeze for future family-building goals. Elective oocyte cryopreservation is increasing in popularity as more women delay family building. By undertaking elective oocyte freezing at a younger age, women hope to optimize their likelihood of successful live birth(s) using their thawed oocytes at a future date. Questions often arise in clinical practice regarding the number of cryopreserved oocytes sufficient to achieve live birth(s) and whether or not additional stimulation cycles are likely to result in a meaningful increase in the likelihood of live birth. As relatively few women who have electively cryopreserved oocytes have returned to use them, available data for counseling patients wishing to undergo fertility preservation are limited. A model was developed to determine the proportion of mature oocytes that fertilize and then form blastocysts as a function of age, using women with presumably normal ovarian reserve based on standard testing who underwent ICSI cycles in our program from January, 2011 through March, 2015 (n = 520). These included couples diagnosed exclusively with male-factor and/or tubal-factor infertility, as well as cycles utilizing egg donation. Age-specific probabilities of euploidy were estimated from 14 500 PGS embryo results from an external testing laboratory. Assuming survival of thawed oocytes at 95% for women <36 y and for egg donors, and 85% for women ≥36 y, and 60% live birth rate per transferred euploid blastocyst, probabilities of having at least one, two or three live birth(s) were calculated. First fresh male-factor and/or tubal-factor only autologous ICSI cycles (n = 466) were analyzed using Poisson regression to calculate the probability that a mature oocyte will become a blastocyst based on age. Egg donation cycles (n = 54) were analyzed and incorporated into the model separately. The proportion of blastocysts expected to be euploid was determined using PGS results of embryos analyzed via array comparative genomic hybridization. A counseling tool was developed to predict the likelihood of live birth, based on individual patient age and number of mature oocytes. This study provides an evidence-based model to predict the probability of a woman having at least one, two or three live birth(s) based on her age at egg retrieval and the number of mature oocytes frozen. The model is derived from a surrogate population of ICSI patients with uncompromised ovarian reserve. A user-friendly counseling tool was designed using the model to help guide physicians and patients. The data used to develop the prediction model are, of necessity, retrospective and not based on patients who have returned to use their cryopreserved oocytes. The assumptions used to create the model, albeit reasonable and data-driven, vary by study and will likely vary by center. Centers are therefore encouraged to consider their own blastocyst formation and thaw survival rates when counseling patients. Our model will provide a counseling resource that may help inform women desiring elective fertility preservation regarding their likelihood of live birth(s), how many cycles to undergo, and when additional cycles would bring diminishing returns. None. Not applicable.

OBJECTIVE: To investigate the relationship between endometriosis and adverse pregnancy outcomes.METHODS: Women between ages 25 and 42 years in 1989 (n=116,429) reported detailed information on pregnancies and reproductive health at baseline and every 2 years thereafter in the Nurses' Health Study II, a cohort study. In 2009, they completed a detailed, pregnancy-focused questionnaire. A total of 196,722 pregnancies were reported. Adverse pregnancy outcomes included spontaneous abortion, ectopic pregnancy, stillbirth, gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (preeclampsia or gestational hypertension), preterm birth, and low birth weight. We estimated the relative risks (RRs) and 95% CIs of adverse pregnancy outcomes comparing pregnancies in women with and without a history of laparoscopically confirmed endometriosis using multivariable log-binomial regression, with generalized estimating equations to account for multiple pregnancies per woman.RESULTS: Endometriosis was associated with a greater risk of pregnancy loss (spontaneous abortion: RR 1.40, 95% CI 1.31–1.49; ectopic pregnancy: RR 1.46, 95% CI 1.19–1.80). Endometriosis was also associated with a greater risk of GDM (RR 1.35, 95% CI 1.11–1.63) and hypertensive disorders of pregnancy (RR 1.30, 95% CI 1.16–1.45).CONCLUSIONS: We observed an association between laparoscopically confirmed endometriosis and several adverse pregnancy outcomes. Future research should focus on the potential biological pathways underlying these relationships to inform screening or preventive interventions.