Endometriosis and Risk of Coronary Heart Disease

In the paper

“Endometriosis has been linked to systemic chronic inflammation, heightened oxidative stress and an atherogenic lipid profile.”

What the sources say

• ?Not checked — no full text of the sourcecites [4] source
• ?Not checked — no full text of the sourcecites [5] source
• Partly supported

  The Discussion states that endometriosis is associated with a chronic immunoinflammatory reaction frequently observed at both local and systemic levels. The paper does not address heightened oxidative stress or an atherogenic lipid profile; searches for oxidative stress and lipid-profile terms returned no supporting passages. No page number was available in our copy. (LLM, conf=0.90)

  cites [6] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [8] source
• ?Not checked — no full text of the sourcecites [9] source
• ?Not checked — no full text of the sourcecites [10] source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [11]

In the paper

“while a study in 10 countries observed an average delay of 6.7 years.(29)”

What the sources say

• Supported

  The Results (Endometriosis: Care-Seeking Experience) report a diagnostic delay of 6.7 years in women with endometriosis. The Abstract (Setting) identifies 16 clinical centers in ten countries. (LLM, conf=0.94)

  cites [29] source

In the paper

“Chr9p21 encodes the long non-coding RNA(ncRNA) ANRIL, which has been demonstrated to regulate cell proliferation, adhesion and apoptosis,(43, 44) - central mechanisms of atherogenesis (13, 43) and endometriosis. (2, 3)”

What the sources say

• Supported

  The Introduction identifies ANRIL as a long non-coding RNA encoded at chromosome 9p21. The Results and Discussion report that ANRIL affects proliferation, adhesion, and apoptosis and describe these as mechanisms of atherogenesis. In the citing sentence, endometriosis has separate citations (2, 3), so it is not attributed to this source. (LLM, conf=0.93)

  cites [43] source
• Partly supported

  The Introduction identifies ANRIL as a non-coding RNA gene at 9p21, and the Results and Discussion link ANRIL expression to cell-cycle regulators in vascular smooth muscle cells. The paper also associates 9p21 variation with smooth muscle cell proliferation in atherosclerosis, but it does not demonstrate that ANRIL regulates adhesion or apoptosis. The citing sentence attributes its endometriosis point to other references, not this source. (LLM, conf=0.86)

  cites [44] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [13] source
• ?Not checked — no full text of the sourcecites [2] source
• ?Not checked — no full text of the sourcecites [3] source

In the paper

“The surgically-induced menopause prior to a natural menopause may increase risk of CHD among women, and this elevated risk may be most evident at a younger age (i.e., before all women reach natural menopause). (20-24)”

What the sources say

• Partly supported

  The Results (no page supplied) associate bilateral oophorectomy before age 45 with increased cardiovascular mortality, supporting the concern about surgery before natural menopause. But the study measured deaths rather than CHD incidence, found no increase in CHD mortality considered separately, and examined mortality many years after surgery; it does not establish that the elevated risk is most evident while women are younger. (LLM, conf=0.87)

  cites [20] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [21] source
• Supported

  The Results report higher CHD mortality after bilateral oophorectomy than after ovarian conservation, including a significant increase among women who had hysterectomy before age 50. They also report higher CHD mortality in the under-50 subgroup who had never used estrogen therapy. The paper cautions that mortality results were not statistically different when stratified by age, so the claim’s tentative 'may be most evident' is appropriate. (LLM, conf=0.88)

  cites [22] source
• Supported

  The Results (p. 3) report increased coronary heart disease incidence associated with hysterectomy and oophorectomy in women under 50, but not an increased risk in the older group. The Discussion (p. 5) says the adverse cardiovascular associations were notable only in younger women and suggests surgical menopause may explain them. This supports the citing sentence’s hedged claim. (LLM, conf=0.92)

  cites [23] source
• Partly supported

  The paper says that surgery well before natural menopause may affect cardiovascular function, and its Results report higher overall cardiovascular disease rates among women with a history of hysterectomy. It does not show that coronary heart disease risk is greatest at younger ages: the cohort was postmenopausal and aged 50–79, and the Results report no significant association for the specified coronary outcomes (MI or coronary death). Page numbers are unavailable in our copy. (LLM, conf=0.84)

  cites [24] sourceExperimental — accuracy not yet measured

In the paper

“Loss of ovarian function and subsequent deficiency of endogenous estrogens may be the biologic mechanism for association between bilateral oophorectomy and cardiovascular diseases, while simple hysterectomy can interfere with ovarian blood flow and may result in premature ovarian failure.(23)”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [23] source

In the paper

“A nationwide study from Sweden showed that hysterectomy without oophorectomy was associated with an increased risk of cardiovascular diseases in women age<50 but not in women age ≥50.(23, 24)”

What the sources say

• Supported

  The Methods and results (p. 1) describe a nationwide Swedish cohort and report increased CVD risk after hysterectomy without oophorectomy among women under 50 at study entry. They report no significant association between hysterectomy and incident CVD among women aged 50 or above at study entry. (LLM, conf=0.94)

  cites [23] source
• Partly supported

  The Discussion (p. 1468) reports that hysterectomy without oophorectomy was associated with higher CVD risk in unadjusted analysis, but that the association was mostly no longer significant after adjustment for risk factors. This paper analyzes a US Women's Health Initiative cohort, not a nationwide Swedish study, and it does not report the claimed difference between women under and over 50. (LLM, conf=0.87)

  cites [24] sourceExperimental — accuracy not yet measured

In the paper

“bilateral oophorectomy at ages younger than 50 has been associated with an increased incidence and mortality of cardiovascular diseases, although results have been inconclusive for bilateral oophorectomy at ages older than 50.(20-22)”

What the sources say

• Partly supported

  The Results report increased cardiovascular mortality after bilateral oophorectomy before age 45, particularly among women who did not continue estrogen treatment through age 45. The study measured mortality, not cardiovascular disease incidence; its significant finding is for under 45 rather than all women under 50, and the cited passages do not characterize results after age 50 as inconclusive. (LLM, conf=0.88)

  cites [20] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [21] source
• Partly supported

  The Results report increased coronary heart disease mortality among women who had oophorectomy before age 50. They do not establish increased cardiovascular disease incidence, and the paper focuses on mortality after hysterectomy rather than incidence. For older women, the Results say CVD mortality estimates remained elevated at age 60 and above, although mortality outcomes did not differ statistically when stratified by age; this supports uncertainty about an age-specific effect, not a clear older-than-50 contrast. (LLM, conf=0.87)

  cites [22] sourceExperimental — accuracy not yet measured

In the paper

“this validation study determined that the average diagnostic delay (from symptom onset to surgical diagnosis) was 4 years in this cohort”

In the paper

“While 31% of the association could be statistically accounted for by greater frequency and longer duration of postmenopausal hormone use, this was primarily driven by greater frequency and earlier age at hysterectomy/oophorectomy.”

In the paper

“In age and calendar year adjusted analyses, the relative risks - comparing women with laparoscopically-confirmed endometriosis (n = 11,903 by end of follow-up) to women without - were 1.63 (95% confidence interval, 1.27 to 2.11) for myocardial infarction, 2.07 (1.73 to 2.47) for angiographically-confirmed angina, 1.49 (1.19 to 1.86) for coronary artery bypass graft surgery/angioplasty/stent and 1.”

In the paper

“The relative risk was highest among women age≤40 (3.08, 2.02 to 4.70) and decreased as age increased (40<age ≤50, 1.65, 1.35 to 2.02; 50<age ≤55, 1.44, 1.07 to 1.94; age >55, 0.98, 0.56 to 1.72; p-value, test for heterogeneity=0.001).”

In the paper

“Results remained statistically significant after adjustment for potential confounders (myocardial infarction, 1.52, 1.17 to 1.98; angina, 1.91, 1.59 to 2.29; coronary artery bypass graft surgery/angioplasty/stent, 1.35, 1.08 to 1.69; combined CHD, 1.62, 1.39 to 1.89) (Table 2).”

In the paper

“thus women with endometriosis are much more likely than the general population to undergo hysterectomy or oophorectomy and also receive the surgery at a much younger age.”

• Also stated in: § Association between endometriosis and CHD · plain

  “Women with endometriosis were also much more likely to have had a hysterectomy and/or oophorectomy and to have had these at an earlier age, be surgically postmenopausal, and use postmenopausal hormones and analgesics.”

In the paper

“Figure 1 demonstrates that women with endometriosis had a higher absolute incidence rate of combined CHD compared to women without endometriosis across ages before late the 50s; the two absolute incidence rates crossed at ages in the late 50s - after which the two groups had similar incidence rates (Figure 1).”

In the paper

“Women with endometriosis were also much more likely to have had a hysterectomy and/or oophorectomy and to have had these at an earlier age, be surgically postmenopausal, and use postmenopausal hormones and analgesics.”

In the paper

“We observed that the increased risk of CHD in women with endometriosis was greatest among younger women, and there was no increased risk from endometriosis after women reached the late 50s.”

In the paper

“Elevated concentration of low-density lipoprotein enhances its retention under the arterial wall(17); retention and oxidation of low-density lipoprotein are fundamental events in atherogenesis.(18)”

What the sources say

• ?Not checked — no full text of the sourcecites [17] source
• ?Not checked — no full text of the sourcecites [18] source

In the paper

“Moreover, women with endometriosis have been suggested to have higher serum levels of low-density lipoprotien (10-12) but lower high-density lipoprotein. (10, 11)”

What the sources say

• ?Not checked — no full text of the sourcecites [10] source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [11]
• ?Not checked — no full text of the sourcecites [12] source

In the paper

“Increasing evidence supports that reactive oxygen species contributes to the process of atherogenesis, as important mediators of signaling pathways that lead to vascular inflammation.(15)”

What the sources say

• ?Not checked — no full text of the sourcecites [15] source

In the paper

“The response rate across the 20 years since enrollment has been consistently over 90% for each questionnaire cycle and did not vary by endometriosis status.”

In the paper

“Non-fatal myocardial infarctions were classed as “confirmed” if they met the criteria of the World Health Organization: symptoms and either diagnostic electrocardiographic changes or raised cardiac enzymes,(30)”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [30]

In the paper

“Results were also unchanged when multiple imputation was applied instead of the missing indicator method to address missing data in any covariate.”

In the paper

“Fatal myocardial infarction was confirmed by hospital records, the National Death Index, or autopsy.”

In the paper

“Clinicians blinded to the questionnaire information reviewed medical records from self-reported non-fatal myocardial infarction events.”

In the paper

“Therefore, we also applied marginal structural models with inverse probability weighting to adjust for potential time-dependent confounding.”

In the paper

“Missing covariate values were handled by the missing indicator method.(31) Multiple imputation to handle the missing data also was performed as a sensitivity analysis.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [31]

In the paper

“we stratified the association between endometriosis and combined CHD by age groups (<40, 40-50, 50-55, ≥55), and tested the statistical significance of the interaction between age and endometriosis with likelihood ratio tests.(33)”

What the sources say

• ?Not checked — no full text of the sourcecites [33] source

In the paper

“Studies also have suggested an increase of markers of oxidative stress but a decrease of antioxidants in the peritoneal fluid (8, 9) and peripheral blood (10, 11) among women with endometriosis.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] source
• ?Not checked — no full text of the sourcecites [9] source
• ?Not checked — no full text of the sourcecites [10] source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [11]

In the paper

“Therefore, the presence of endometriosis may promote coronary artery atherosclerosis formation and progression, increasing the risk of CHD.”

In the paper

“In contrast, high-density lipoprotein is antiatherogenic, removing cholesterol from cells in the arterial intima.(19)”

What the sources say

• ?Not checked — no full text of the sourcecites [19] source

In the paper

“to further account for risk factors of hysterectomy, we added adjustment for household income, husband's education and geographic region of residence. We also further adjusted for potential indication for hysterectomy including infertility history and analgesics use (in addition to oral contraceptive) as indicators of endometriosis clinical severity.”

In the paper

“The longitudinal study design, large sample size and 20 years of follow-up allowed us to document the prospective association between surgically diagnosed endometriosis and subsequent risk of CHD.”

In the paper

“The mediation proportion estimated from this model can be interpreted as the mediation proportion to be observed in this study population or any other study population with a similar proportion of treatment and a similar age distribution.”

In the paper

“as Zondervan (51) et al. quantified, the likely prevalence of undiagnosed endometriosis should not exceed 2% of the unexposed population, and therefore too low to impact on the results, particularly in our large study population among whom undiagnosed endometriosis become diluted among tens of thousands of those with no endometriosis.”

What the sources say

• ?Not checked — no full text of the sourcecites [51] source

In the paper

“our unexposed group (i.e. never clinically or surgically diagnosed with endometriosis) may include asymptomatic endometriosis or symptomatic without confirmatory diagnosis. If so, our results would be biased toward the null.”

In the paper

“Moreover, because the results of multivariable Cox models and marginal structural models were almost identical, the potential bias that may remain within multivariable Cox models for adjustment of time-varying confounding (32) was negligible.”

What the sources say

• ?Not checked — no full text of the sourcecites [32] source

In the paper

“It is possible that the observed increased risk associated with surgical menopause from hysterectomy/oophorectomy among women with endometriosis started to diminish with age partially because nearly every woman had reached menopause by age 55.”

In the paper

“Finally, the timing of exposure was defined by time of surgical diagnosis, not disease onset.”

In the paper

“Hysterectomy/oophorectomy was associated with higher risk of CHD and could explain a portion of the association between endometriosis and CHD.”