{"paper_id":"79444c8a-82a6-44ac-9250-ca92376795f0","body_text":"Endometriosis is a chronic and estrogen-dependent gynecologic disorder that\naffects ~10% of women of reproductive age in the United States.( 1 ) It is defined as the presence of\nendometrium-like tissue thriving outside the uterus, primarily on the pelvic\nperitoneum and ovaries.( 2 ) Signs and symptoms\ninclude chronic pelvic pain, dysmenorrhea, dyspareunia, and reduced fertility.( 3 )\nEndometriosis has been linked to systemic chronic inflammation, heightened\noxidative stress and an atherogenic lipid profile. Various inflammatory factors,\ne.g. interleukin-1, interleukin-6, tumor necrosis factor-α, have been\nobserved to be elevated both in peritoneal fluid ( 4 - 6 ) and the peripheral blood\n( 4 ,  5 ,  7 ) of women with endometriosis\ncompared to controls. Studies also have suggested an increase of markers of\noxidative stress but a decrease of antioxidants in the peritoneal fluid ( 8 ,  9 ) and\nperipheral blood ( 10 ,  11 ) among women with endometriosis. Moreover, women with\nendometriosis have been suggested to have higher serum levels of low-density\nlipoprotien ( 10 - 12 ) but lower high-density lipoprotein. ( 10 ,  11 )\nInflammation, oxidative stress and an atherogenic lipid profile play key\nroles in the pathogenesis of atherosclerotic CHD.( 13 - 15 ) Chronic systemic\ninflammation contributes to vascular insult and atheromatous plaque\nprogression.( 16 ) Increasing evidence\nsupports that reactive oxygen species contributes to the process of atherogenesis,\nas important mediators of signaling pathways that lead to vascular\ninflammation.( 15 ) Elevated concentration\nof low-density lipoprotein enhances its retention under the arterial wall( 17 ); retention and oxidation of low-density\nlipoprotein are fundamental events in atherogenesis.( 18 ) In contrast, high-density lipoprotein is antiatherogenic, removing\ncholesterol from cells in the arterial intima.( 19 ) Therefore, the presence of endometriosis may promote coronary artery\natherosclerosis formation and progression, increasing the risk of CHD.\nIn addition, the treatments of endometriosis, such as hysterectomy or\noophorectomy ( 20 - 24 ) and analgesics ( 25 )\nmay confer increased risk of CHD to women with endometriosis. Hysterectomy or\noophorectomy is a surgical treatment for endometriosis, thus women with\nendometriosis are much more likely than the general population to undergo\nhysterectomy or oophorectomy and also receive the surgery at a much younger age. The\nsurgically-induced menopause prior to a natural menopause may increase risk of CHD\namong women, and this elevated risk may be most evident at a younger age (i.e.,\nbefore all women reach natural menopause). ( 20 - 24 )\nIn sum, women with endometriosis may have higher risk of CHD compared to\nwomen without endometriosis,( 26 ) and this\nassociation may differ by age group. To test these hypotheses, we examined the\nprospective associations between endometriosis and myocardial infarction,\nangiographically-confirmed angina, and coronary artery bypass graft surgery/coronary\nangioplasty procedure/stent within the Nurses’ Health Study II, a large\nprospective cohort study.\n\nNurses’ Health Study II is a prospective cohort study with 116,430\nregistered female nurses who were 25 to 42 and resided in 14 of the United\nStates at enrollment in 1989. At baseline, participants completed a detailed\nquestionnaire regarding demographic, medical, lifestyle, reproductive and other\ninformation and have continued to do so biennially. This research was approved\nby the Institutional Review Boards of Brigham and Women's Hospital and Harvard\nT.H. Chan School of Public Health, Boston, MA, USA.\nIn 1993, women were first asked if they had “ever had\nphysician-diagnosed endometriosis.” If “yes,” they were\nasked during which two year follow-up period the diagnosis had occurred and if\nit had been confirmed by laparoscopy–the gold standard for diagnosing\nendometriosis.( 27 ,  28 ) They were asked again in each\nsubsequent biennial questionnaire.\nAs previously detailed, ( 1 ) the\nsurgical report validation for self-reported laparoscopically-confirmed\nendometriosis cases within this cohort is 96% (n=101/105). Among women without\nlaparoscopic confirmation, evidence of clinical diagnosis or symptoms was found\nin only 54% (n=14/26) of the records. Thus, self-reported physician-diagnosed\nendometriosis without laparoscopic confirmation may be substantially\nmisclassified, and therefore, endometriosis exposure was restricted to women who\nreported laparoscopic confirmation. Those who reported endometriosis diagnosis\nbut never laparoscopic confirmation were censored at the report of clinical\ndiagnosis. In addition, this validation study determined that the average\ndiagnostic delay (from symptom onset to surgical diagnosis) was 4 years in this\ncohort, while a study in 10 countries observed an average delay of 6.7\nyears.( 29 ) A shorter diagnostic delay\nwithin Nurses’ Health Study II compared to the general population may be\nattributed to the medical knowledge and greater access to care of this cohort of\nregistered nurses.\nWe assessed incident myocardial infarction cases (fatal and non-fatal),\nangiographically-confirmed angina and coronary artery bypass graft\nsurgery/angioplasty/stent cases that occurred between enrollment and the 2007\nquestionnaire cycle (which ended in May 2009). Clinicians blinded to the\nquestionnaire information reviewed medical records from self-reported non-fatal\nmyocardial infarction events. Non-fatal myocardial infarctions were classed as\n“confirmed” if they met the criteria of the World Health\nOrganization: symptoms and either diagnostic electrocardiographic changes or\nraised cardiac enzymes,( 30 ) as\n“probable” if hospital records were not obtained but they were\ncorroborated in writing or a telephone interview. Fatal myocardial infarction\nwas confirmed by hospital records, the National Death Index, or autopsy.\nPhysician-diagnosed angina confirmed by angiography, coronary artery bypass\ngraft surgery/angioplasty/stent and time of diagnosis were self-reported. When\nmyocardial infarction, angiography-confirmed angina and coronary artery bypass\ngraft surgery/angioplasty/stent cases were combined as the outcome (the combined\nCHD), we used the time of the first CHD event among those three to define the\nfirst age of occurrence.\nThose who experienced myocardial infarction, stroke,\nangiographically-confirmed angina or coronary artery bypass graft\nsurgery/angioplasty/stent prior to enrollment into Nurses’ Health Study\nII in 1989 were excluded from this study. Person-months at risk were calculated\nfrom age at enrollment to age at death, CHD incidence, and end of follow-up for\nthe present aims, whichever occurred first.\nAs the main analysis, we quantified the association between\nendometriosis and CHD using multivariable Cox proportional hazards models.\nTo evaluate potential confounding, we adjusted for age at the beginning of\neach questionnaire cycle and calendar time and then additionally adjusted\nfor demographic, anthropometric, family history, reproductive, and lifestyle\npotential confounders including known risk factors for CHD to calculate\ncrude and adjusted relative risks and 95% confidence intervals. All\ntime-varying covariates were updated prospectively. Given that most\nquestions were asked in every questionnaire across the nearly 20 years of\nfollow-up, we observed little missing data. For example, there were less\nthan 1% missing data for age at menarche (asked at baseline) and smoking\nhistory (asked in each questionnaire) among 2,019,360 person-years. The\nhighest percentage of missing values observed was for birth weight (5%),\nbody mass index (5%) and postmenopausal hormone use (6%). Missing covariate\nvalues were handled by the missing indicator method.( 31 ) Multiple imputation to handle the missing data also\nwas performed as a sensitivity analysis. Standard multivariable Cox models\nmay be biased when there exist time-dependent confounders that are also\naffected by previous exposure.( 32 )\nFor example, diet and physical activity change over time and can be\ninfluenced by previous endometriosis diagnosis. Therefore, we also applied\nmarginal structural models with inverse probability weighting to adjust for\npotential time-dependent confounding.\nSecondly, we examined if and how age modifies the association\nbetween endometriosis and CHD. To do so, we stratified the association\nbetween endometriosis and combined CHD by age groups (<40, 40-50,\n50-55, ≥55), and tested the statistical significance of the\ninteraction between age and endometriosis with likelihood ratio tests.( 33 ) We plotted the absolute incidence\nrate of combined CHD against age for women with and without\nlaparoscopically-confirmed endometriosis, calculated by multivariable\nadjusted pooled logistic regression. This incidence rate was calculated at\nthe mean or mode of all covariates.\nThirdly, we investigated the relationship between endometriosis,\nhysterectomy/oophorectomy and combined CHD. As the first step, we assessed\nthe association between hysterectomy/oophorectomy and combined CHD. In\naddition to the covariates adjusted in the main analysis, to further account\nfor risk factors of hysterectomy, we added adjustment for household income,\nhusband's education and geographic region of residence. We also further\nadjusted for potential indication for hysterectomy including infertility\nhistory and analgesics use (in addition to oral contraceptive) as indicators\nof endometriosis clinical severity.\nAs the second step, we calculated if proportions of the association\nbetween endometriosis and combined CHD could be statistically accounted for\nby the surgical treatments hysterectomy/oophorectomy. To do so, we added\nadjustment for hysterectomy/oophorectomy to the base multivariate model\n(i.e. now a surgery-adjusted model). Then, we calculated the proportion of\nthe association between endometriosis and combined CHD that was\nstatistically accounted for by hysterectomy/oophorectomy by dividing the log\nrelative risk for combined CHD in relation to endometriosis estimated from\nthe surgery-adjusted model by the log relative risk for combined CHD in\nrelation to endometriosis from the base model. Confidence intervals for\nthese estimated proportions account are calculated as per Lin et al. ( 34 ). We repeated this method to\ncalculate the proportions of association between endometriosis and combined\nCHD that were statistically accounted for by postmenopausal hormone use\n(estrogen, progesterone/progestin, or estrogen and progesterone/progestin\ncombined) and duration of use, and analgesic use.\n\nAt baseline in 1989, 116,430 women were enrolled in this cohort. The\nresponse rate across the 20 years since enrollment has been consistently over\n90% for each questionnaire cycle and did not vary by endometriosis status.\nDuring the 20 years follow up among 1,971,574 person-years, there were 1,438\nincident combined CHD cases. At baseline (1989), women who had\nlaparoscopically-confirmed endometriosis history (n = 5,296) were slightly\nolder, had earlier age at menarche, were more likely to be nulliparous, had\nlower parity, were more likely to use oral contraceptives and more likely to\nhave a family history of myocardial infarction <age 60 years old,\ncompared to women who had not been diagnosed with endometriosis at baseline\n( Table 1 ). Women\nwith endometriosis were also much more likely to have had a hysterectomy and/or\noophorectomy and to have had these at an earlier age, be surgically\npostmenopausal, and use postmenopausal hormones and analgesics.\nIn age and calendar year adjusted analyses, the relative risks -\ncomparing women with laparoscopically-confirmed endometriosis (n = 11,903 by end\nof follow-up) to women without - were 1.63 (95% confidence interval, 1.27 to\n2.11) for myocardial infarction, 2.07 (1.73 to 2.47) for\nangiographically-confirmed angina, 1.49 (1.19 to 1.86) for coronary artery\nbypass graft surgery/angioplasty/stent and 1.73 (1.49 to 2.00) for combined CHD\n( Table 2 ). Results\nremained statistically significant after adjustment for potential confounders\n(myocardial infarction, 1.52, 1.17 to 1.98; angina, 1.91, 1.59 to 2.29; coronary\nartery bypass graft surgery/angioplasty/stent, 1.35, 1.08 to 1.69; combined CHD,\n1.62, 1.39 to 1.89) ( Table\n2 ). Results were unchanged when using marginal structural models.\nResults were also unchanged when multiple imputation was applied instead of the\nmissing indicator method to address missing data in any covariate. The\nsignificant association between endometriosis and combined CHD remained after\nadjustment for each treatment factor.\nWe observed a statistically significant interaction between\nendometriosis and age for the combined CHD endpoint. The relative risk was\nhighest among women age≤40 (3.08, 2.02 to 4.70) and decreased as age\nincreased (40<age ≤50, 1.65, 1.35 to 2.02; 50<age\n≤55, 1.44, 1.07 to 1.94; age >55, 0.98, 0.56 to 1.72; p-value,\ntest for heterogeneity=0.001).  Figure\n1  demonstrates that women with endometriosis had a higher\nabsolute incidence rate of combined CHD compared to women without endometriosis\nacross ages before late the 50s; the two absolute incidence rates crossed at\nages in the late 50s - after which the two groups had similar incidence rates\n( Figure 1 ). The\nincidence rate difference between women with endometriosis and women without\nendometriosis increased slowly as age increased until around age 50.\nWe observed that women who had a hysterectomy/oophorectomy had higher\nage-standardized incidence rates of CHD. Having had a hysterectomy/oophorectomy\nwas associated with higher age-standardized absolute incidence rates of CHD\ncompared to those who had not: 139 vs. 60 per 100,000 person years; having had a\nhysterectomy/oophorectomy was associated with higher risk of combined CHD\ncompared to not having had a hysterectomy/oophorectomy (1.51, 1.34 to 1.71).\nAdjustment for potential risk factors and indication for\nhysterectomy/oophorectomy did not attenuate this association.\nWe observed that 42% of the association between endometriosis and CHD\nwas statistically significantly accounted for by greater frequency of\nhysterectomy/oophorectomy and earlier age at these surgeries among women with\nendometriosis ( Table 3 ).\nWhile 31% of the association could be statistically accounted for by greater\nfrequency and longer duration of postmenopausal hormone use, this was primarily\ndriven by greater frequency and earlier age at hysterectomy/oophorectomy.\n\nCompared to women without endometriosis, laparoscopically-confirmed\nendometriosis was associated with a significantly increased risk of myocardial\ninfarction, angiographically-confirmed angina, and coronary artery bypass graft\nsurgery/angioplasty/stent. Adjustment for potential confounders did not attenuate\nthis association. Hysterectomy/oophorectomy was associated with a higher risk of CHD\nand explained a portion of the association between endometriosis and CHD.\nTo our knowledge, this is the first prospective cohort study investigating\nthe association between endometriosis and CHD. One case-control study found null\nresults when investigating whether women with endometriosis (n=66) had greater\nsubclinical atherosclerosis than controls (n=66), measured by intima-media thickness\non the common carotid artery.( 36 ) As noted by\nthe author, the mean age of the study population was only 41 years. Given the small\nsample size, the study had insufficient statistical power to detect increased\natherosclerosis at such early age. Also, the control group was defined as women with\nuterine myomas, ovarian cysts or pelvic pain, who may have greater risk of\nsubclinical atherosclerosis than the general population. Another case control study\nalso investigated the association between carotid intima-media thickness and\nendometriosis and found null results.( 37 )\nHowever, this study similarly had a very young age group (mean age 33 in cases and\n35 in controls) and very small sample size (37 cases and 31 controls).\nSystemic chronic inflammation, heightened oxidative stress and atherogenic\nlipid profile associated with endometriosis and the synergistic effect of the three\nmay underpin the biologic mechanism for the association between endometriosis and\nCHD. Additionally, endometriosis and CHD may share common genetic susceptibilities.\nMultiple independent loci in the CDKN2BAS1 (also known as ANRIL) region on\nchromosome 9p21 have been robustly associated with endometriosis in genome-wide\nassociation studies in Japanese and European ancestry populations,( 38 ,  39 )\nand has also been robustly associated with CHD outcomes.( 40 - 42 ) Chr9p21 encodes\nthe long non-coding RNA(ncRNA) ANRIL, which has been demonstrated to regulate cell\nproliferation, adhesion and apoptosis,( 43 ,\n 44 ) - central mechanisms of atherogenesis\n( 13 ,  43 ) and endometriosis. ( 2 ,  3 )\nApart from these biologic mechanisms, it is possible that the crude\nassociation between endometriosis and CHD can be explained by CHD risk factors that\npredate and cause endometriosis (for example, diet). However, the small attenuation\nof relative risk from the crude models to the comprehensive multivariable models\nsuggests that strong confounding is unlikely. Moreover, because the results of\nmultivariable Cox models and marginal structural models were almost identical, the\npotential bias that may remain within multivariable Cox models for adjustment of\ntime-varying confounding ( 32 ) was\nnegligible.\nWe observed that the increased risk of CHD in women with endometriosis was\ngreatest among younger women, and there was no increased risk from endometriosis\nafter women reached the late 50s. This association may have important clinical and\npublic health implications among women in their early 40s to early 50s. It is\npossible that the observed increased risk associated with surgical menopause from\nhysterectomy/oophorectomy among women with endometriosis started to diminish with\nage partially because nearly every woman had reached menopause by age 55.\nWe observed higher risk of CHD among women who had a\nhysterectomy/oophorectomy compared to women who did not have a\nhysterectomy/oophorectomy. These associations were not altered when potential\nconfounding factors, e.g., age, parity, BMI, race/ethnicity ( 45 - 47 ), were adjusted\nfor in the multivariable analyses. Another important determinant of the decisions\nregarding hysterectomy/oophorectomy is education ( 45 ,  47 ), which is very homogenous\nin this population of nurses, and so we additionally adjusted for husband's\neducation level and household income, again with no evidence of confounding.\nConfounding by indication of this hysterectomy association could be due to severity\nof endometriosis disease. Therefore, we further adjusted for infertility history and\nanalgesics use (in addition to oral contraceptive use) as proxies of endometriosis\ndisease severity as the main presentations of endometriosis are infertility and pain\n( 1 ,  3 ). Adjustment did not change the association between\nhysterectomy/oophorectomy and CHD. These results were supported by the literature:\nbilateral oophorectomy at ages younger than 50 has been associated with an increased\nincidence and mortality of cardiovascular diseases, although results have been\ninconclusive for bilateral oophorectomy at ages older than 50.( 20 - 22 ) A nationwide\nstudy from Sweden showed that hysterectomy without oophorectomy was associated with\nan increased risk of cardiovascular diseases in women age<50 but not in women\nage ≥50.( 23 ,  24 ) Loss of ovarian function and subsequent deficiency of\nendogenous estrogens may be the biologic mechanism for association between bilateral\noophorectomy and cardiovascular diseases, while simple hysterectomy can interfere\nwith ovarian blood flow and may result in premature ovarian failure.( 23 )\nWe observed that approximately 40% of the observed significant association\nbetween endometriosis and CHD may be statistically accounted for by\nhysterectomy/oophorectomy and age at surgery. This may be because 1) women with\nendometriosis were subsequently much more likely to have a hysterectomy/oophorectomy\nand had the surgery at a younger age compared to women without endometriosis; and 2)\nhysterectomy/oophorectomy is associated with higher risk of CHD. The mediation\nproportion estimated from this model can be interpreted as the mediation proportion\nto be observed in this study population or any other study population with a similar\nproportion of treatment and a similar age distribution. The remaining ~50% of\nthe significant association between endometriosis and CHD was not explained by\nendometriosis treatments.\nThese data raise concerns regarding treating endometriosis with\nhysterectomy/oophorectomy. Physicians need to consider the potential long term\nimpact that the surgeries may cause and weigh the risks and benefits of the\ntreatment in dialogue with patients, particularly with respect to endometriosis\nwhere pain recurrence risk remains.( 48 )\nAlthough oophorectomy confers obvious prevention for ovarian cancer, with which\nendometriosis has been associated ( 49 ), CHD\nis the leading cause of mortality and morbidity in women in the US and UK. CHD\nincidence and mortality are orders of magnitude greater than ovarian cancer, with\nincidence 30 times greater and mortality 26 times greater in the US in 2010.( 50 ) However, we acknowledge that endometriosis\nmanagement decisions are not random, and there are many individual issues that\ncontribute to treatment decisions between a physician and patient.\nRegarding limitations, our unexposed group (i.e. never clinically or\nsurgically diagnosed with endometriosis) may include asymptomatic endometriosis\nor symptomatic without confirmatory diagnosis. If so, our results would be\nbiased toward the null. However, in sensitivity analyses expanded definition of\nendometriosis cases by attributing person time from endometriosis without\nlaparoscopic confirmation to the exposed group did not alter the results. More\nimportantly, as Zondervan ( 51 ) et al.\nquantified, the likely prevalence of undiagnosed endometriosis should not exceed\n2% of the unexposed population, and therefore too low to impact on the results,\nparticularly in our large study population among whom undiagnosed endometriosis\nbecome diluted among tens of thousands of those with no endometriosis. We did\nnot have information on other hormonal treatments for endometriosis, such as\ndanazol (a synthetic androgen) and Leuprolide (lupron, gonadotropin-releasing\nhormone analog) to assess to what extent the association between endometriosis\nand CHD could have been explained by those treatments. We also did not have\ninformation on the extent of excision of endometriosis lesions during\nlaparoscopy to evaluate whether the excision could alter the elevated CHD risk\nassociated with endometriosis, although no current cohort of sufficient size has\nthese data. Regarding generalizability, these medical professionals have greater\nknowledge of and access to medical care, minimizing misclassification of the\nprimary exposure (endometriosis) or the outcomes and thus maximizing precision\nof hazard ratio estimation, it is unlikely that the underlying biologic relation\nobserved between endometriosis and CHD, if true, would differ between these\nwomen and women in the general population. Finally, the timing of exposure was\ndefined by time of surgical diagnosis, not disease onset. However, this is true\nfor all studies of endometriosis regardless of design; furthermore, sensitivity\nanalyses predating diagnosis time of endometriosis for 2, 4, 6 or 8 years didn't\nchange our results.\nOur study has many strengths. The longitudinal study design, large\nsample size and 20 years of follow-up allowed us to document the prospective\nassociation between surgically diagnosed endometriosis and subsequent risk of\nCHD. The wealth of time-varying data allowed for detailed adjustment for known\nand suspected potential confounders and risk factors for CHD. Minimal\nconfounding was seen. We were able to assess proportions of the association\nstatistically accounted for by various treatment factors. Lastly, the results\nwere robust across multiple definitions of CHD.\n\nIn this large prospective cohort, laparoscopically-confirmed endometriosis\nwas associated with higher risk of CHD. The association was stronger among young\nwomen. Hysterectomy/oophorectomy was associated with higher risk of CHD and could\nexplain a portion of the association between endometriosis and CHD. These data have\nimplications for clinical management of endometriosis patients, suggesting women\nwith endometriosis may represent a high risk group for CHD -- particularly at a\nyoung age, indicating the need for risk awareness and subsequent screening for CHD\nand healthy lifestyle promotion among primary care and public health\nspecialists.","source_license":"CC0","license_restricted":false}