Background: Body mass index (BMI) is a risk factor for endometrial cancer. We quantified the risk and investigated whether the association differed by use of hormone replacement therapy (HRT), menopausal status, and histologic type.

Methods: We searched MEDLINE and EMBASE (1966 to December 2009) to identify prospective studies of BMI and incident endometrial cancer. We did random-effects meta-analyses, meta-regressions, and generalized least square regressions for trend estimations assuming linear, and piecewise linear, relationships.

Results: Twenty-four studies (17,710 cases) were analyzed; 9 studies contributed to analyses by HRT, menopausal status, or histologic type, all published since 2003. In the linear model, the overall risk ratio (RR) per 5 kg/m(2) increase in BMI was 1.60 (95% CI, 1.52-1.68), P < 0.0001. In the piecewise model, RRs compared with a normal BMI were 1.22 (1.19-1.24), 2.09 (1.94-2.26), 4.36 (3.75-5.10), and 9.11 (7.26-11.51) for BMIs of 27, 32, 37, and 42 kg/m(2), respectively. The association was stronger in never HRT users than in ever users: RRs were 1.90 (1.57-2.31) and 1.18 (95% CI, 1.06-1.31) with P for interaction = 0.003. In the piecewise model, the RR in never users was 20.70 (8.28-51.84) at BMI 42 kg/m(2), compared with never users at normal BMI. The association was not affected by menopausal status (P = 0.34) or histologic type (P = 0.26).

Conclusions: HRT use modifies the BMI-endometrial cancer risk association.

Impact: These findings support the hypothesis that hyperestrogenia is an important mechanism underlying the BMI-endometrial cancer association, whilst the presence of residual risk in HRT users points to the role of additional systems.