This study analyzed associations between various demographic, clinical, and laboratory variables and CA125 levels in both premenopausal and postmenopausal women without history of OC in a large nationally representative sample. CA125 level has been reported to be higher in pre- versus postmenopausal women and decreases with advancing age [17, 26]. Our results were consistent. In agreement with prior studies, [17, 18] this study also found that CA125 levels were lower in non-White compared to White women. Study participants with higher BMI had lower CA125 concentration, consistent with findings from previous studies that obesity was associated with lower CA125 level, likely due to the dilution effect of high plasma volume [18, 27].

Of the reproductive/gynecologic history variables examined, hysterectomy history was not significantly associated with CA125 levels in the multivariable analyses in postmenopausal women, though the crude linear regression did show an inverse relationship (− 8.06%, p = 0.05), which is consistent with the results of prior studies suggesting that hysterectomy history may be associated with lower CA125 level [17, 18]. In premenopausal women, this study demonstrated that 5–10 years’ duration of OCP use, compared to duration < 2 years, was less likely to be associated with CA125 level ≥ 35 U/ml. Sasamoto et al. had shown that longer duration of OCP use (> 4 years), compared to duration < 2 years, was associated with lower CA125 level in premenopausal women without OC [19]. This finding correlates with the duration-dependent protective association between longer OCP use and risk reduction of OC by suppressing ovulation [28,29,30]. This study found that postmenopausal women with breastfeeding history were more likely to be associated with CA125 level ≥ 35 U/ml. To our knowledge, there has been no prior literature reporting on the direct relationship between breastfeeding and CA125 level. Breastfeeding has been reported to be associated with 24% decrease in risk of ovarian cancer; the protective mechanism is hypothesized to be the inhibition of epithelial cell in the setting of ovulation suppression during breastfeeding [31]. The association between breastfeeding and CA125 revealed in this study seems to be contrary to expectation, which may reflect a true association between breastfeeding history and CA125 level in women without OC, or may reflect bias from small sample size in the analysis (N = 23 who had CA125 level ≥ 35 U/ml in postmenopausal subgroup) or the choice of cut-off value for CA125.

Higher CA125 levels have been reported in women with active endometriosis, and CA125 was even proposed as a candidate screening biomarker for endometriosis [32, 33]. However, among postmenopausal women, history of endometriosis has been reported to be associated with lower CA125 level, [7, 9] likely reflecting the resolution of endometriosis after menopause or management. This study similarly demonstrated that in premenopausal women, self-reported diagnosis of endometriosis was associated with higher CA125 levels, although this association was not retained in multivariable linear or logistic analyses. This study also showed that in postmenopausal women, history of endometriosis was associated with lower CA125 levels in univariable linear regression. However, the significance disappeared in multivariable analysis, and logistic regressions could not be performed due to sample size limitation. One explanation is that in postmenopausal women, measurement of CA125 can reflect not only the presence/absence of a historical gynecologic diagnosis, but also the subsequent clinical management and current status of the condition, whether it remains active.

In terms of bone health, osteoporosis was significantly associated with lower CA125 levels in premenopausal women by crude linear regression (− 31.13%, p = 0.049) and showed similar trend in postmenopausal women via both univariable linear regression (− 1.69%, p = 0.750) and logistic regression (OR = 0.938, p = 0.905). This finding was consistent with previously reported positive correlation between bone mineral density and CA125 level in both pre- and postmenopausal women [34], reflecting a lower CA125 level in setting of hypoestrogenic state contributing to decreased bone density. For postmenopausal women, Akinwunmi et al. had demonstrated that both osteoporosis and osteoarthritis were associated with lower levels of CA125, [9] however our study did not reveal such significant associations (N = 76 for osteoporosis and N = 225 for osteoarthritis in Akinwunmi’s study, versus N = 203 for osteoporosis and N = 175 for osteoarthritis in this study).

Regarding cardiovascular comorbidities, this study showed decreased levels of CA125 in premenopausal women with CAD in crude linear regression (− 49.79%, p = 0.001). This finding contradicts Akinwunmi et al’s study in which CA125 was reported to be higher in premenopausal women with CAD based on a very small number of CAD cases (N = 2 versus N = 10 in present study) [9]. Given the rarity of CAD in young women, interpretation of the association between CA125 level and CAD in the premenopausal setting is difficult. For postmenopausal women, history of CAD was associated with higher CA125 levels in the multivariable linear regression model (28.27%, p = 0.047) and more likely to be associated with CA125 level ≥ 35 U/ml in multivariable logistic regression (OR = 5.00, p = 0.011); these findings are in agreement with prior literature [9, 35]. Other studies have suggested that increased CA125 may be associated with heart failure and pericardial effusions, hypothesizing that higher levels of CA125 are secreted from pericardium in the setting of mechanical stretch, irritation, and inflammation [36, 37]. The association between CAD and increased CA125 in postmenopausal women might be explained by the level of active or uncontrolled cardiac inflammation or decompensated heart failure at the particular cross-sectional time-point of this study.

To explore the relationship between inflammation and CA125 level, laboratory biomarkers of inflammation (CRP and ferritin) were included in this study. As a protein produced by coelomic epithelial cells lining the pleura, peritoneum and ovaries in the setting of inflammatory stress, CA125 level was hypothesized to demonstrate positive association with inflammatory biomarkers [9, 38]. The study showed that increasing CRP level correlated with higher levels of CA125 by crude linear regressions in both premenopausal and postmenopausal subgroups, and significantly increased the odds of having CA125 level ≥ 35 U/ml by multivariable logistic analysis in the postmenopausal subgroup. No association between ferritin level and CA125 level was demonstrated regardless of menopausal status.

History of non-ovarian cancer was found to be associated with higher CA125 levels in premenopausal women. In postmenopausal women, those with non-ovarian cancer history tended toward a lower likelihood of having CA125 levels ≥ 35 U/ml. Funston et al. have reported in a UK population-based study that 12.3% of those with CA125 level ≥ 35 U/ml were diagnosed with a non-ovarian cancer, and non-ovarian cancer diagnosis was found in 20.4% of women with CA125 level ≥ 35 U/ml who were ≥ 50 years of age [39].The results from our postmenopausal group deviated from such findings, perhaps reflecting some component of prior cancer-directed management and/or difference stemming from this study examining the US population. As noted, information regarding cancer diagnosis in this study was based on interview questions, and more specific details about the cancer diagnosis such as the time of diagnosis, whether or not the cancer is active, and treatment history could not be ascertained. Some of those who recorded a history of non-ovarian cancer in our study might have been cured a long time ago with CA125 levels falling within normal range at the time of study measurement. As such, the real association between non-ovarian cancer and CA125 level, especially in postmenopausal women, might be masked or diminished in this analysis. Moreover, this study did not examine the relationships between each specific non-ovarian cancer and CA125 level. Study participants reported history of major non-ovarian cancers including breast cancer (24%), non-melanoma skin cancer (20%), cervical cancer (14%), colon cancer (7%), lung cancer (3%), lymphoma (2%), stomach cancer (1%), and liver cancer (0.5%). Given the known strong association between breast cancer and higher CA125 levels as previously reported, [9] further investigation of breast cancer history and CA125 level was done, using crude linear regression. Breast cancer history was found to have a potentially marginal association with higher CA125 level in premenopausal women (N = 7, effect estimate = 0.63, p = 0.082) but did not reach any statistical significance in postmenopausal women (N = 41, p = 0.985).

Current smoking was associated with lower CA125 level among premenopausal women in both multivariable linear and logistic regressions, consistent with previous findings [17, 18]. Smoking has been postulated to potentiate hepatic enzymes which accelerate metabolic degradation of CA125 [17]. In postmenopausal women only, more than 2 drinks a day was associated with lower CA125 in crude linear regression. No previous studies have evaluated the relationship between alcohol consumption and CA125 level. Perhaps severe alcohol consumption may upregulate hepatic metabolism of CA125, resulting in its serum decline. This study also found that in postmenopausal women only, more caffeine intake was associated with lower CA125 level after adjusting for baseline confounding variables, which is consistent with Pauler et al’s findings that caffeine consumption decreased CA125 level [17].

This study has several unique strengths. First, study participants comprised a nationally representative sample from across the United States. Results from this data are more generalizable compared to results from control groups in previous studies, which were more restricted in terms of the ethnicities, ages and/or geographies represented. Furthermore, those study enrollees from long-term cancer screening or prevention clinical trials tended to be generally healthier compared to the general population [40]. Another strength is the inclusion of both premenopausal and postmenopausal women, allowing for clearer comparisons in two subgroups. Both linear regression and logistic regression methods facilitated multivariable adjustments, enabling confirmation of significant associations between CA125 level and multiple candidate factors, and increasing the precision of analyses from these different dimensions. The linear regressions could be used to evaluate trends over time either for potential screening for early detection of OC or disease surveillance and monitoring response to therapy in patients with OC. The dichotomized method utilizing a cutoff value to define abnormally elevated CA125 generates more data for an approach to interpreting CA125 results as a clinical screening biomarker in a previously unscreened population. Moreover, this study examined further the relationship between CAD and CA125 level, which has not been explored in depth in existing literature. Associations between history of CAD with CA125 levels stratified by menopausal status in this study differed from those previously published in literature, suggesting the need to re-examine reported associations given limitations in sample sizes of studies to date. Finally, this is the one of the first few studies to examine the relationship between clinical biomarkers of inflammation and CA125 levels.

We acknowledge several limitations of this study. The cross-sectional design did not allow for longitudinal measurements of CA125 and precluded interpretation of CA125 trends over time. Study participants provided only a snapshot of their clinical history and lifestyle practices at one particular point in time via self-report without further validation. The clinical data obtained regarding participants’ medical conditions, especially with respect to the non-ovarian cancer diagnosis, may not have reflected the actual status of such medical conditions. Whether a participant was in remission, receiving treatment, or progressing at the moment when CA125 level was measured, and how long ago the treatment was given, cannot be confirmed. As such, this analysis was unable to eliminate the confounding effect related to the status of non-ovarian cancer diagnoses and other medical conditions, and the real associations might be underestimated. It is interesting to note, however, that Akinwunmi et al. previously found no evidence that treatments associated with a particular medical condition changed the association between the medical condition and CA125 level [9]. Additionally, this study does not include all the possible factors that may affect CA125 levels, so these results may be biased by unmeasured or unknown confounders. For instance, BRCA mutation status and family history of OC could not be assessed, although increased CA125 level has been associated with BRCA mutations and familial OC [5]. Other factors, such as history of heart failure, cirrhosis, and the specific menstrual cycle phase of each study participant at time of survey, which have been reported to impact CA125 levels could not be included here [9, 41,42,43]. Some potential correlating factors, such as the use of intrauterine device with hormones, history of pelvic inflammatory disease and polycystic ovary syndrome, were not included in the questionnaire of NHANES 2001–2002. Additionally, under-diagnosis of benign gynecologic diseases such as uterine fibroids and endometriosis is common, especially in asymptomatic patients, and may contribute to masking certain associations. Furthermore, the choice of cut-off value for CA125 would potentially impact the study results. We used 35 U/ml as a cutoff based on recommendations of National Institute for Health and Care Excellence (NICE); this cutoff was derived from a prior study in which only 1% of apparently healthy persons, 6% of patients with nonmalignant disease, and 82% of patients with surgically demonstrated ovarian cancer had a CA125 level ≥ 35 U/ml [2, 25]. Funston et al. has reported that a cut-off value of 23 U/ml provided a higher sensitivity but lower specificity (86.4% and 86%) compared to standard cut-off (35 U/ml) (78.5% and 94.5%) for ovarian cancer diagnosis, in a retrospective cohort study examining routinely collected primary care and cancer registry data from the UK [44]. By performing logistic regressions based on this new cut-off (433 participants with CA125 level ≥ 23 U/ml), comparable findings were demonstrated, consistent with that generated from using the cutoff of 35 U/ml. In premenopausal women, longer OCP use and current use of CHC were more likely to be associated with CA125 level ≥ 23 U/ml by multivariable logistic regression; history of endometriosis was associated with CA125 level ≥ 23 U/ml in univariable logistic regression only. In postmenopausal women, relatively similar associations were found in crude analyses, especially that elevated CRP level significantly increased the odds of having CA125 level ≥ 23 U/ml; however, none of these potential variables reached significance in multivariable regression analyses (see supplementary tables). Similar exposure factors could lead to fluctuations in CA125 levels when 23 U/ml was applied as the cut-off, supplying a rationale for the reduced specificity of 23 U/ml as the cut-off for an elevated CA125 level in Funston et al’s study. Finally, these results were based on sampling participants in 2001–2002, and may no longer be reflective of current associations between CA125 levels and various candidate correlating factors, given changes in disease demographics, management, and lifestyle practices over time.

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