Insulin resistance and endometrial cancer risk in postmenopausal women by race and body mass index

Mihae Song; Rowan Chlebowski; Joanne Mortimer; Kathy Pan; Thomas Rohan; Hailey Banack; Su Yon Jung; Juhua Luo; Lihong Qi; Fred Tabung; Robert Wallace; Robert Wild; Rebecca Nelson

doi:10.1016/j.ygyno.2025.04.028

Objectives While insulin resistance has been associated with several cancers, data regarding its associations with endometrial cancer have been limited, especially in Black women. Therefore, we evaluated the association of insulin resistance, as measured using the homeostatic model assessment of insulin resistance (HOMA-IR), with endometrial cancer incidence and mortality, with a particular focus on Black postmenopausal women participating in the Women's Health Initiative (WHI). Methods Eligible participants included 22,672 WHI participants aged 50–79 years enrolled at 40 U.S. clinical centers with baseline fasting glucose and insulin levels. Endometrial cancers were verified by central medical record review and mortality findings were enhanced by serial national death index queries. The primary study variable was baseline HOMA-IR tertile. Hazard ratios for endometrial cancer incidence and mortality were calculated using multivariable Cox proportional hazards models, with adjustment for age, race, ethnicity, body mass index (BMI), recreational activity, alcohol use and use of estrogen and progestin hormone therapy. Results Included participants were 58.4 % white, 35.2 % Black and 6.4 % other/unknown women; of these, 15.4 % were Hispanic. Women in the lowest HOMA-IR tertile were less often Black, had lower BMI and were more likely current smokers and alcohol users (all P < 0.001). During the median 23.6-year follow-up period, with 185 endometrial cancers and 28 associated deaths, HOMA-IR was associated with higher endometrial cancer incidence (Tertile [T] 3 vs T1, HR 1.99, 95 % CI 1.27–3.13, trend P = 0.005). With limited numbers, endometrial cancer-specific mortality was not associated with HOMA-IR. In white women, the HOMA-IR association with endometrial cancer was: (T3 vs T1, 1.89 (1.08–3.32), trend P = 0.03). In Black women, findings were similar (T3 vs T1, HR 2.17, 95 % CI 1.00–4.72, trend P = 0.06). Considering all participants, HOMA-IR was associated with endometrial cancer risk with BMI levels ≥25 kg/m2 (T3 vs T1, HR 1.98, 95 % CI 1.19–3.27, trend P = 0.01) but not with BMI levels 18–25 kg/m2, (T3 vs T1, HR 2.34, 95 % CI 0.52–10.66, trend P = 0.20). Conclusions Insulin resistance, as measured by HOMA-IR, was associated with higher endometrial cancer risk with similar findings in both white and Black postmenopausal women. These findings will help Identify women who could potentially benefit from early detection and intervention strategies.

Insulin resistance and endometrial cancer risk in postmenopausal women by race and body mass index

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