Risk factors for atypical hyperplasia and endometrial cancer in the infertility population: a case-control study.

A total of 11,569 women met inclusion and exclusion criteria, 22 of whom were diagnosed with AH or EC, thus defining the incidence of AH or EC as 2 per 1,000 women (95% confidence interval [CI] 1.2–2.9 per 1,000 women). Of these 22 cases, 12 were diagnosed with AH (incidence 0.10%) and 10 were diagnosed with EC (incidence 0.10%). All women with EC had FIGO (International Federation of Gynecology and Obstetrics) staging system grade I endometrioid adenocarcinoma at time of diagnosis. Demographics of the cases and controls are shown in Table 1 . The median age of cases and controls was 35 years (interquartile range 32–38 years) and 34 years (interquartile range 31–37 years), respectively. Sixty-four percent of women in the cohort were White, 21% African American, and 15% Other races. African American women were overrepresented among cases (n = 8/22, 36%) compared with controls (n = 43/220, 20%). Cases were also significantly more likely to be obese (15/22, 68% vs. 54/220, 25%). Unadjusted analysis also demonstrated higher rates of nulliparity (21/22, 95% vs. 173/220, 79%), chronic hypertension, (6/22, 27% vs. 17/220, 8%), and diabetes mellitus (2/22, 9% vs. 6/220, 3%) among cases compared with controls, although absolute numbers were small in several cells. Table 1 Demographic characteristics of the study population. Characteristic Cohort (n = 242) Controls (n = 220) Cases (n = 22) P value Age (y) 34 (31–37) 34 (31–37) 35 (32–38) .601 Race  White 156 (64) 144 (65) 12 (55) .065  African American 51 (21) 43 (20) 8 (36)  Other 35 (15) 33 (15) 2 (9) BMI ≥30 kg/m 2 69 (29) 54 (25) 15 (68) <.001 Nulliparous 194 (80) 173 (79) 21 (95) .088 Previous OCP use 104 (44) 97 (45) 7 (32) .246 Current smoker 39 (16) 33 (15) 6 (27) .135 Diabetes 8 (3) 6 (3) 2 (9) .158 Hypertension 23 (10) 17 (8) 6 (27) .003 Hypothyroidism 37 (15) 33 (15) 4 (18) .699 Note: Data are reported as median (interquartile range). All other data are reported as n (%). BMI = body mass index; OCP = oral contraceptive pill. Demographic characteristics of the study population. Note: Data are reported as median (interquartile range). All other data are reported as n (%). BMI = body mass index; OCP = oral contraceptive pill. Reproductive characteristics of cases and controls are described in Table 2 . Cases had a longer duration of infertility (23 vs. 12 months) compared with controls. Cases were more likely to be diagnosed with ovulatory dysfunction (11/22, 50% vs. 56/220, 25%), likely due to a higher prevalence of PCOS (8/22, 36% vs. 42/220, 19%). The etiologies of ovulatory dysfunction among cases were limited to PCOS, pituitary dysfunction, hypothyroidism, and obesity, most of which (73%) were secondary to PCOS. There were no cases with ovulatory dysfunction attributable to hypothalamic hypogonadism. Cases were also more likely to report abnormal uterine bleeding (12/22, 55% vs. 34/220, 34%), have an abnormal HSG (12/22, 55% vs. 31/220, 31%), and/or an abnormal TVUS (15/22, 68% vs. 52/220 24%) compared with controls. Table 2 Reproductive characteristics of the study population. Characteristic Cohort (n = 242) Controls (n = 220) Cases (n = 22) P value Duration of infertility (mo) 12 (9–24) 12 (9–24) 23 (12–36) .068 Infertility diagnosis  Diminished ovarian reserve 53 (22) 49 (22) 4 (18) .658  Ovulatory dysfunction 67 (28) 56 (25) 11 (50) .014  Tubal factor 29 (12) 28 (13) 1 (5) .488  Uterine factor 45 (19) 39 (18) 6 (27) .273  Unexplained 83 (34) 80 (36) 3 (14) .032  Endometriosis 16 (7) 14 (6) 2 (9) .624 PCOS 50 (21) 42 (19) 8 (36) .056 History of AUB 83 (36) 71 (34) 12 (55) .054 Prior fertility treatment 46 (11) 40 (18) 6 (27) .305 Abnormal HSG 81 (33) 69 (31) 12 (55) .028 Abnormal ultrasound 67 (28) 52 (24) 15 (68) <.001 Note: Data are reported as median (interquartile range). All other data are reported as n (%). AUB = abnormal uterine bleeding; HSG = hysterosalpingogram; PCOS = polycystic ovarian syndrome. Reproductive characteristics of the study population. Note: Data are reported as median (interquartile range). All other data are reported as n (%). AUB = abnormal uterine bleeding; HSG = hysterosalpingogram; PCOS = polycystic ovarian syndrome. Results of the logistic regression are shown in Table 3 . After adjusting for age, African American race, and presence of ovulatory dysfunction, women with BMI ≥30 kg/m 2 were 5.9 times more likely to be diagnosed with AH or EC (adjusted odds ratio [AOR] 5.9, 95% CI 2.0–17.2). Patients with ovulatory dysfunction were 3.4 times more likely to be diagnosed with AH and/or EC (AOR 3.4, 95% CI 1.1–10.1) when controlling for age, African American race, and BMI. Patient age and African American race were not independently associated with odds of AH or EC after controlling for BMI. When analyses were stratified by BMI, patients with ovulatory dysfunction and BMI ≥30 kg/m 2 were 7.25 times more likely to be diagnosed with AH and/or EC (AOR 7.25, 95% CI 1.6–32.1). In women with normal BMI and ovulatory dysfunction, we found that there was no significant association with a diagnosis of AH and/or EC (AOR 0.68, 95% CI 0.07–7.01) ( Table 4 ). When analyses were stratified by presence of ovulatory dysfunction, patients with ovulatory dysfunction and BMI ≥30 kg/m 2 were significantly more likely to be diagnosed with AH and/or EC (AOR 23.30, 95% CI 2.32–233.97). Obese patients without ovulatory dysfunction also trended toward an increased risk for AH and/or EC, but the confidence interval was broad and not found to be statistically significant (AOR 3.11, 95% CI 0.80–12.18) ( Table 4 ). Given the complex relationship between these two risk factors, a Pearson correlation coefficient analysis was performed and demonstrated a correlation coefficient of 0.28 for BMI ≥30 kg/m 2 and 0.16 for ovulatory dysfunction. Table 3 Multivariate analysis of risk factors for atypical endometrial hyperplasia and endometrial cancer in the population with infertility. Risk factor OR AOR 95% CI P value BMI ≥30 kg/m 2 6.59 5.88 2.01–17.19 .001 Ovulatory dysfunction 2.93 3.36 1.11–10.18 .032 African American race 2.35 0.814 0.27–2.44 .713 Age 1.03 1.07 0.96–1.19 .198 Note: After adjusting for remaining covariates (age, African American race, BMI ≥30 kg/m 2 , ovulatory dysfunction). AOR = adjusted odds ratio; BMI = body mass index; CI = confidence interval; OR = odds ratio. Table 4 Stratified analysis of risk factors. Risk factor Normal weight (BMI <30 kg/m 2 ) Obese (BMI ≥30 kg/m 2 ) No ovulatory dysfunction Ovulatory dysfunction AOR a 95% CI P value AOR a 95% CI P value AOR a 95% CI P value AOR a 95% CI P value BMI ≥30 kg/m 2 — — — — — — 3.11 0.80–12.18 .103 23.30 2.32–233.97 .007 Ovulatory dysfunction 0.68 0.07– 7.01 .747 7.25 1.64– 32.13 .009 — — — — — — African American race b 0.87 0.25– 2.99 .821 0.55 0.10–3.07 .497 0.90 0.18– 4.49 .894 Age 1.06 0.87– 1.29 .557 1.09 0.96–1.24 .204 1.07 0.92–1.24 .404 1.09 0.94–1.28 .261 a After adjusting for remaining covariates (age, African American race, BMI ≥30 kg/m 2 , ovulatory dysfunction). AOR = adjusted odds ratio; BMI = body mass index; CI = confidence interval. b There are no African American cases in the normal weight group, therefore race was dropped from this model. Multivariate analysis of risk factors for atypical endometrial hyperplasia and endometrial cancer in the population with infertility. Note: After adjusting for remaining covariates (age, African American race, BMI ≥30 kg/m 2 , ovulatory dysfunction). AOR = adjusted odds ratio; BMI = body mass index; CI = confidence interval; OR = odds ratio. Stratified analysis of risk factors. After adjusting for remaining covariates (age, African American race, BMI ≥30 kg/m 2 , ovulatory dysfunction). AOR = adjusted odds ratio; BMI = body mass index; CI = confidence interval. There are no African American cases in the normal weight group, therefore race was dropped from this model.

The study population included female patients aged 18–50 years who were seen for an infertility evaluation between January 2009 and December 2018 in the Division of Reproductive Endocrinology and Infertility at the University of Pennsylvania and Pennsylvania Hospital. Patients who had a TVUS and/or an HSG were included in the analysis. Patients with a known genetic predisposition to cancer or a prior diagnosis of uterine, ovarian, breast, or colon cancer were excluded. Cases were defined as patients with a pathology confirmed diagnosis of AH or EC on endometrial sampling. The diagnosis was identified using International Classification of Disease 9 and 10 codes 621.33 (endometrial hyperplasia with atypia), 621.35 (endometrial intraepithelial neoplasm), N85.02 (endometrial intraepithelial neoplasm), 179 (malignant neoplasm corpus uteri—unspecified site), C55 (malignant neoplasm corpus uteri—unspecified site), 182.0 (malignancy corpus uteri except isthmus), and C54.1 (malignant neoplasm of endometrium). The aims of our study were addressed separately due to the descriptive nature of our first aim and the comparative nature of our second aim. Cases were used to calculate the incidence in the population of women undergoing routine infertility evaluation. For our comparative study, controls were defined as women without AH or EC who were diagnosed with any female factor or unexplained infertility. Cases were matched to randomly selected controls in a 1:10 ratio by year of infertility evaluation based on a sample size calculation demonstrating that 10 controls per case provides 80% power to detect an odds ratio of 3.93 for AH or EC with α = 0.05 ( Supplemental Fig. 1 , available online). Patient demographics, reproductive history, and relevant medical history data were abstracted and entered into a secure REDCap database. Female age was dichotomized as <35 and ≥35 years, body mass index (BMI) as <30 and ≥30 kg/m 2 , and parity as 0 versus ≥1 births. Race was categorized as White, African American, and Other for initial data acquisition; however, was later dichotomized to African American and Other for ease of statistical analysis given our small sample size and race distribution. Infertility diagnoses were categorized as diminished ovarian reserve, ovulatory dysfunction, tubal factor, uterine factor, unexplained infertility, and endometriosis. Presence or absence of polycystic ovarian syndrome (PCOS) was documented separately. Other abstracted data included age at menarche (years), oral contraceptive pill use (yes/no) duration of infertility (months), prior fertility treatments (yes/no), history of abnormal uterine bleeding (yes/no), presence of normal versus abnormal imaging results (TVUS and HSG), and pathology results from endometrial sampling obtained during the infertility evaluation. The study was approved by the Institutional Review Board at the University of Pennsylvania. The incidences of AH and EC were calculated by dividing the number of cases by the total population with infertility. Univariate statistics were generated using χ 2 and Fisher’s exact test for categorical variables and Student’s t -test or Wilcoxon rank sum test for continuous variables as appropriate. Logistic regression modeling was used to estimate the odds of AH or EC. Forward selection was used to account for covariates. Tests for colinearity were performed for BMI and ovulatory dysfunction with no collinearity identified in the study population. The final model accounted for age, African American race, BMI, and presence of ovulatory dysfunction. Statistical analysis was performed by using STATA 14.2.

The present study demonstrates an incidence of EC or AH diagnosed on a routine infertility evaluation of 2 per 1,000 women (0.1%), approximately 10 times higher than the reported incidence in comparably aged women in the general population in the United States ( 1 ). Adjusted analysis revealed obesity (BMI ≥30 kg/m 2 ) was the strongest risk factor for developing AH or EC (AOR 5.9, 95% CI 2.0–17.2), independent of age, race, and ovulatory dysfunction. In addition, ovulatory dysfunction was found to be a risk factor with affected patients being 3.4 times more likely to have AH or EC. Although obesity and ovulatory dysfunction were not found to be collinear in the study population, both play a role in the risk of developing AH and/or EC with obesity as the primary driver of this relationship. Stratified analyses further revealed that the risk of AH and/or EC among women with ovulatory dysfunction was modified by BMI. Although women with ovulatory dysfunction and BMI ≥30 kg/m 2 were 7.25 times more likely to be diagnosed with AH and/or EC, no association was seen among those with BMI <30 kg/m 2 . Therefore in patients with ovulatory dysfunction, not being obese was protective against an AH and/or EC diagnosis. Similar to findings in prior studies on EC in the general population, exposure to unopposed estrogen is associated with most cases of AH and/or EC in our population. Our cases were more often nulliparous and had longer duration of infertility compared with controls. Ovulatory dysfunction due to PCOS was more prevalent among cases, and although not statistically significant, this association is relevant clinically when assessing risk factors in patient encounters. Prevalence of chronic hypertension and/or diabetes mellitus diagnoses were also higher among cases, which is likely explained by concurrent obesity. In the general population, oral contraceptive pill use and/or smoking are protective factors against the development of EC; however, this was not demonstrated in our population. Much of the current knowledge regarding AH and/or EC among reproductive-aged women has been extrapolated from the gynecologic oncology literature on pregnancy outcomes for women with AH and/or EC undergoing fertility-sparing treatment. In one small retrospective cohort study ( 7 ) determining the outcomes of fertility-sparing treatment with progestin therapy for AH and EC in women <40 years old, 73% of women reported being diagnosed with infertility. Rackow et al. ( 5 , 6 ) have suggested that women undergoing infertility evaluation are at increased risk of developing EC compared with age-matched counterparts due to prolonged unopposed estrogen exposure associated with nulliparity, ovulatory dysfunction, PCOS, and/or obesity. In addition, studies suggest that infertility may be more common among young patients with AH or EC due to potentially impaired embryo implantation ( 5 ). There is limited literature on AH and EC diagnosed incidentally among patients presenting for an infertility workup, and no studies have examined this question in an American population. Fujiwara et al. ( 8 ) describe six cases of AH and/or EC found within 19,826 women undergoing routine infertility investigations in Japan between 2007 and 2016. They reported an incidence of 0.03% and 0.02% for AH and EC, respectively, in their population, which is 5–10 times higher than the overall incidence in Japan. This series is limited by its small sample size and homogeneous population in a country with a low baseline prevalence of AH and/or EC. Likewise, Tohma et al. ( 9 ) investigated the prevalence of AH and/or EC in women seen for an infertility evaluation in Turkey. In their study, 5,560 patients underwent endometrial biopsy or hysteroscopy based on symptoms or ultrasound findings, and 10 (0.18%) were diagnosed with EC and 17 (0.3%) were diagnosed with AH. Although this is the highest prevalence reported in the literature for a reproductive age group, these data only reflect the prevalence of AH and EC within the subpopulation of infertility patients with symptoms or imaging that prompted endometrial sampling rather than all patients presenting for an infertility evaluation. Given that not all patients in our infertility population received endometrial sampling, we are unable to comment on prevalence of disease in the entire infertile population. A strength of the present study is its inclusion of an unrestricted sample of patients with female infertility, therefore allowing calculation of baseline AH and/or EC incidence and quantification of risk factors in an otherwise asymptomatic cohort. The study is further strengthened by the racial diversity of the infertility population, thus increasing generalizability of the results to the American population at large. Although the high incidence of AH and/or EC in the present study may be due to over-representation of obesity and ovulatory dysfunction in the infertile population, investigational bias may also play a role ( 8 ). Outside of an infertility evaluation, it is rare for a young, asymptomatic, patient to undergo uterine cavity assessment or endometrial sampling. In an infertility evaluation, detailed uterine cavity assessment is routine, although endometrial sampling is only performed in the setting of focal findings or symptoms ( 10 ). Current best practice guidelines recommend endometrial sampling for patients aged 19–45 years with abnormal uterine bleeding and exposure to unopposed estrogen. Patients >45 years old should be sampled for abnormal uterine bleeding alone ( 11 ). Accordingly, the 45% of cases in our study who did not report abnormal uterine bleeding would have experienced a delayed diagnosis without an infertility evaluation. There are currently no recommendations for endometrial sampling in asymptomatic patients with other risk factors and further research is needed to determine the utility of risk-based screening in this population. The retrospective design of this study carries other inherent biases and limitations. There is potential for a type II error given our small sample size. It is also possible that the true incidence of AH and/or EC in patients undergoing routine infertility evaluation was overestimated or underestimated due to inaccurate coding within the electronic medical record. Some patients had incomplete information within the electronic medical record, particularly when infertility evaluation was started at our institution but not continued. Last, the case-control study design does not enable us to assess change in incidence of AH and/or EC over time. In summary, the present study found a 10-fold increase in the incidence of AH and/or EC among women undergoing routine infertility evaluation compared with aged women in the general population. Unsurprisingly, obesity was identified as the strongest risk factor for AH and/or EC within this population with infertility. Our data would suggest that physicians should maintain an index of suspicion for AH and EC in even a younger patient with infertility who presents with obesity and/or ovulatory dysfunction. Prospective studies are needed, however, to determine whether selective endometrial sampling based on obesity alone would increase detection of early endometrial pathology in the population of women undergoing an infertility evaluation.