Female Reproductive Traits and Late-Life Hormone-Sensitive Cancer Risk: A Mendelian Randomization Study

Ovarian reserve is a crucial component of female reproductive traits. However, the possible causal effects between ovarian reserve and hormone-sensitive cancers remain incompletely understood. Two-sample Mendelian randomization analyses (MR) were performed to assess potential causal effects of reproductive traits on hormone-sensitive cancers. In addition, multivariable MR was applied to determine the potential mediation effects of reproductive traits on hormone-sensitive cancers. A one SD incremental increase in the anti-Müllerian hormone (AMH) level was associated with a higher risk of endometrial cancer (OR = 1.27, 95% CI = 1.05-1.54) but a lower risk of breast cancer (OR = 0.80, 95% CI = 0.69-0.94). Each 1-year incremental increase in age at natural menopause was associated with higher risks of breast (OR = 1.04, 95% CI, 1.02-1.05), ovarian (OR = 1.03, 95% CI, 1.01-1.05), and endometrial cancers (OR = 1.07, 95% CI, 1.04-1.09). Nulliparity increased the risk of breast cancer (OR = 1.07, 95% CI, 1.05-1.09). An elevated AMH level was indirectly associated with endometrial cancer risk with 2.67% of the effect attributed to later age at natural menopause (per 1-year increase). Each 1-year incremental increase in age at menarche was indirectly associated with endometrial cancer risk with 4.71% of the effect attributed to later age at natural menopause. The findings herein highlight AMH as a potential key biological marker for endometrial and breast cancer risk. Identifying natural menopause as a key modulator may enhance our understanding of the mechanisms underlying hormone-sensitive cancers.